U S M L E®
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
USMLE® is a joint program of the Federation of State Medical Boards (FSMB) and the
National Board of Medical Examiners (NBME), neither of which sponsors or endorses this product.
U SM L E®
Lecture Notes 2018
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
USMLE® is a joint program of the Federation of State Medical Boards (FSMB) and the National Board of Medical Examiners (NBME), neither of which sponsors or endorses this product.
This publication is designed to provide accurate information in regard to the subject matter covered as of its publication date, with the understanding that knowledge and best practice constantly evolve. The publisher is not engaged in rendering medical, legal, accounting, or other professional service.
Published by Kaplan Medical, a division of Kaplan, Inc. 750 Third Avenue
New York, NY 10017
All rights reserved. The text of this publication, or any part thereof, may not be reproduced in any manner whatsoever without written permission from the publisher.
10 9 8 7 6 5 4 3 2 1
Course ISBN: 978-1-5062-2818-1 Retail Kit ISBN: 978-1-5062-2080-2
This item comes as a set and should not be broken out and sold separately.
Kaplan Publishing print books are available at special quantity discounts to use for sales promotions,
employee premiums, or educational purposes. For more information or to purchase books, please call the SUiSmMoLnE®&iSscahjuosintetrpsrpogecraiaml soaflTehsedFeepdaertramtieonntoaftS8t6a6te-5M0e6d-i1c9a4l9B.oards of the United States, Inc.
and the National Board of Medical Examiners.
Editors
Joseph J. Lieber, MD Associate Director of Medicine Elmhurst Hospital Center
Associate Professor of Medicine
Associate Program Director in Medicine for Elmhurst Site Icahn School of Medicine at Mt. Sinai
Assistant Professor of Internal Medicine
Site Director, Internal Medicine Clerkship and Sub-Internship Icahn School of Medicine at Mt. Sinai
Hospitalist Elmhurst Hospital Center
The editors would like to acknowledge
Manuel A. Castro, MD, AAHIVS, Amirtharaj Dhanaraja, MD, and Aditya Patel, MD, and Irfan Sheikh, MD for their contributions.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
We want to hear what you think. What do you like or not like about the Notes?
Please email us at medfeedback@kaplan.com.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
00
Table of Contents
Chapter Title
Chapter 1: Preventive Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Chapter 2: Endocrinology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Chapter 12: Dermatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433
Chapter 13: Radiology/Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
Chapter 14: Ophthalmology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473
Additional resources available at www.kaptest.com/usmlebookresources
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
v
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
PreventCivheapMtedr iTciitnle #1
Learning Objectives
Describe appropriate screening methods as they apply to neoplasms of the colon, breast, cervix, and lung
Describe epidemiological data related to incidence and prevention of common infectious disease, chronic illness, trauma, smoking, and travel risks
CANCER SCREENING
Screening tests are done on seemingly healthy people to identify those at increased risk of dis- ease. Even if a diagnostic test is available, however, that does not necessarily mean it should be used to screen for a particular disease.
Several harmful effects may potentially result from screening tests.
Any adverse outcome that occurs (large bowel perforation secondary to a colonoscopy) is iatrogenic.
Screening may be expensive, unpleasant, and/or inconvenient.
Screening may also lead to harmful treatment.
Finally, there may be a stigma associated with incorrectly labeling a patient as “sick.”
For all diseases for which screening is recommended, effective intervention must exist, and the course of events after a positive test result must be acceptable to the patient. Most important, the screening test must be valid, i.e., it must have been shown in trials to decrease overall mortality in the screened population. For a screening test to be recommended for regular use, it has to be extensively studied to ensure that all of the requirements are met.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
1
USMLE Step 2 l Internal Medicine
Note
Tamoxifen prevents cancer by 50% in those with >1 family member with breast cancer.
Note
Prostate Screening
USPSTF concludes that the current evidence is insufficient to assess the balance of benefits/risks of prostate cancer screening in men age
<75. It recommends against screening in men age >75.
For USMLE, do not screen for prostate cancer.
The 4 malignancies for which regular screening is recommended are cancers of the colon, breast, cervix, and lung.
Colon Cancer
In the patient with no significant family history of colon cancer, screening should begin at age
The preferred screening modality for colon cancer is colonoscopy every 10 years. Other choices include annual fecal occult blood testing and sigmoidoscopy with barium enema every 5 years.
In the patient with a single first-degree relative diagnosed with colorectal cancer before age 60 or multiple first-degree relatives with colon cancer at any age, colonoscopy should begin at age 40 or 10 years before the age at which the youngest affected relative was diagnosed, whichever age occurs earlier. In these high-risk patients, colonoscopy should be repeated every 5 years. The U.S. Preventive Services Task Force (USPSTF) does not recommend routine screening in patients age >75.
The tests used to screen for breast cancer are mammography and manual breast exam. Mammography with or without clinical breast exam is recommended every 1–2 years from age 50–74. The American Cancer Society no longer recommends monthly self-breast examination alone as a screening tool. Patients with very strong family histories of breast cancer (defined as multiple first-degree relatives) should consider prophylactic tamoxifen, discussing risks and benefits with a physician. Tamoxifen prevents breast cancer in high-risk individuals.
The screening test of choice for the early detection of cervical cancer is the Papanicolaou smear (the “Pap” test). In average risk women, Pap smear screening should be started at age 21, regardless of onset of sexual activity. It should be performed every 3 years until age 65.
As an alternative, women age 30–65 who wish to lengthen the screening interval to every 5 years can do co-testing with Pap and HPV testing. In higher risk women, e.g., HIV, more frequent screening or screening after age 65 may be required.
Lung Cancer
Current recommendations for lung cancer screening are as follows:
Annual screening with low-dose CT in adults age 55–80 who have a 30-pack-year smoking history and currently smoke or have quit within past 15 years
Once a person has not smoked for 15 years or develops a health problem substantially limiting life expectancy or ability/willingness to have curative lung surgery, screening should be discontinued
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
2
Chapter 1 ● Preventive Medicine
Clinical Recall
Which of the following patients is undergoing an inappropriate method of screening as recommended by the USPSTF?
A 50-year-old man gets his first screening for colon cancer via colonoscopy
A 50-year-old woman gets her first screening for breast cancer via mammography
A 17-year-old woman is screened for HPV via a Pap smear after her first sexual encounter
A 65-year-old man with a 30-pack-year smoking history gets a low- dose CT
A 21-year-old woman with a high risk of developing breast cancer is given tamoxifen
TRAVEL MEDICINE
It is important to set up a pretravel counseling session 4–6 weeks before the patient’s departure.
Hepatitis A infection is travelers’ most common vaccine-preventable disease. Hepatitis
A infection is possible wherever fecal contamination of food or drinking water may occur. Infection rates are particularly high in nonindustrial countries. If a patient is leaving within 2 weeks of being seen, both the vaccine and immune serum globulin are recommended.
A booster shot given 6 months after the initial vaccination confers immunity for approximately 10 years.
All travelers to less-developed countries should get hep A vaccine.
Hepatitis B vaccination is recommended for patients who work closely with indigenous popula- tions. Additionally, patients who plan to engage in sexual intercourse with the local populace, to receive medical or dental care, or to remain abroad for >6 months should be vaccinated.
Malaria: Mefloquine is the agent of choice for malaria prophylaxis. It is given once per week; it may cause adverse neuropsychiatric effects such as hallucinations, depression, suicidal ideations, and unusual behavior. Doxycycline is an acceptable alternative to mefloquine, although photosensitivity can be problematic. For pregnant patients requiring chemoprophy- laxis for malaria, chloroquine is the preferred regimen.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
3
USMLE Step 2 l Internal Medicine
Note
Patients must get Pneumovax, meningococcal, and Haemophilus vaccines 2 weeks before a splenectomy.
Rabies vaccination is recommended for patients traveling to areas where rabies is common among domesticated animals (India, Asia, Mexico). Chloroquine can blunt the response to the intradermal form of rabies vaccine. Therefore, in patients who require malaria prophylaxis, in addition to rabies prophylaxis the intramuscular form of the vaccine should be administered. Rabies vaccination is not considered a routine vaccination for most travelers.
Typhoid vaccination is recommended for patients who are traveling to developing countries and will have prolonged exposure to contaminated food and water. Typhoid vaccination comes in 2 forms, an oral live attenuated form and a capsular polysaccharide vaccine given parenter- ally. The live attenuated form (1) needs to be refrigerated, and (2) is contraindicated in patients who are HIV-positive. The polysaccharide vaccine is given intramuscularly as a single injection. Side effects include irritation at the injection site. Fever and headache are rare adverse reactions to the vaccine. The polysaccharide vaccine is the preferred form for almost all subjects as it is well-tolerated and convenient (no need for refrigeration). It is safe for HIV patients.
Polio: Adults who are traveling to developing countries and have never received a polio vaccine should receive 3 doses of the inactivated polio vaccine. Patients who have been previously immunized should receive a 1-time booster. The live attenuated polio vaccine is no longer recommended because of the risk of vaccine-associated disease.
Patients traveling to areas where meningococcal meningitis is endemic or epidemic (Nepal, sub-Saharan Africa, northern India) should be immunized with the polysaccharide vaccine. Additionally, Saudi Arabia requires immunization for pilgrims to Mecca. Patients with func- tional or actual asplenia and patients with terminal complement deficiencies should also receive the vaccine. Meningococcal vaccine is now routinely administered at age 11.
To prevent traveler’s diarrhea, patients should be advised to avoid raw and street vendor salads, unwashed fruit, and tap/ice water. Patients who experience mild loose stools without fever or blood can safely take loperamide. Treatment with a fluoroquinolone or azithromycin is reserved for patients with moderate to severe symptoms.
A 52-year-old man comes to the clinic for a health maintenance evaluation. His recent colonoscopy showed no evidence of carcinoma. Recent serum fasting glucose, serum cholesterol, and blood pressure are all within normal limits. The patient has a history of smoking and continues to smoke 2 packs per day. He was diagnosed with COPD 3 years ago.
Immunization is the best method available for preventing serious infectious disease. Between 50,000–70,000 adults die every year from preventable infectious disease (influenza, invasive pneumococcal disease, and hepatitis B). Surveys have shown that among patients who have an indication for any vaccination, very few actually receive it (pneumococcal vaccination 20%, influenza 40%, hepatitis B 10%). For this reason, the American College of Physicians recom- mends that every patient’s immunization status be reviewed at age 50; evaluate risk factors for specific vaccinations at that time.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
4
Chapter 1 ● Preventive Medicine
Most patients received a primary immunization against tetanus and diphtheria as children.
For those adults who were never vaccinated, give 3 doses. The principle is that adults require a total of 3 vaccinations against tetanus and diphtheria.
Give the first 2 doses 1−2 months apart
Give the third dose 6–12 months later
Give a booster vaccination every 10 years for life; one of the boosters should use Tdap instead of Td booster. If the wound is dirty, revaccinate after 5 years.
Influenza Vaccine
Influenza vaccines is recommended annually for all adults regardless of age. Patients who have a history of cardiopulmonary disease, diabetes mellitus, or hemoglobinopathy, or are age 50+ residents of chronic care facilities derive the greatest benefit from an annual influenza vaccina- tion. Pregnant women who will be in their second or third trimester during the influenza season should also receive the vaccine.
Pneumococcal vaccine is indicated for all adults age ≥65. Additionally, the following individu- als should receive the vaccine regardless of age:
Those with history of cardiopulmonary disease, alcoholism, or cirrhosis
Immunocompromised patients (patients with hematologic malignancies, chronic renal failure, or nephrotic syndrome; HIV-positive patients; or patients receiving immuno- suppressive medications)
Revaccination should be performed in healthy patients who received their initial vaccination age <65 and were age <60 at the time of primary vaccination. Patients with a high risk of fatal infection (CKD, asplenic patients, immunocompromised patients) should be revaccinated 1x after 5 years. No one gets >1 booster shot per lifetime.
Hepatitis B Vaccine
Hepatitis B vaccine is recommended when there is a history of IV drug abuse, male homo- sexuality, household or sexual contact with hepatitis B carriers, or frequent exposure to blood/ blood products. Additionally, patients with a history of chronic liver disease should receive the vaccine. Immunity is confirmed serologically.
It is also recommended for all children through age 18, those with STIs, those who are sexually active but not monogamous, workers with occupational exposure to blood, and prison inmates.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
5
USMLE Step 2 l Internal Medicine
Hepatitis A Vaccine
The hepatitis A vaccine protects against the virus in >95% of cases. There are 2 types of vaccine, both of which stimulate active immunity against a future infection.
One contains inactivated hepatitis A virus
One contains a live but attenuated virus
For the best protection, give the vaccine in 2 doses: initial dose and then a booster 6–12 months later. Protection against hepatitis A begins approximately 2–4 weeks after the initial vaccination.
In the United States, the vaccine is strongly recommended for all children age 12–23 months in an attempt to eradicate the virus nationwide. There are also recommendations that the fol- lowing populations be vaccinated:
All children age >1 year
People who are being treated with clotting factor concentrates
People who are living in communities where an outbreak is present
Hepatitis A is the most common vaccine-preventable virus acquired during travel, so people travelling to places where the virus is common (Indian subcontinent, Africa, Central America, South America, the far East, and Eastern Europe) should be vaccinated.
The varicella vaccine is a live attenuated vaccine recommended for use in all adults who lack a history of childhood infection with varicella virus. Being a live attenuated vaccine, varicella vaccine should not be given to immunocompromised patients, HIV-positive patients when symptomatic or <200 CD4 cells, or pregnant women.
Patients age ≥60 are recommended to receive the varicella zoster (shingles) vaccine, which has been shown to reduce the risk of zoster and its associated pain (post-herpetic neuralgia). It is indicated regardless of whether there is a history of shingles, as it is possible to have a second herpes zoster infection.
Measles, Mumps, Rubella Vaccine
The measles, mumps, rubella (MMR) vaccine is a live attenuated vaccine usually given in childhood. Healthy adults born after 1956 should receive 1 dose of the vaccine. Pregnant women and immunocompromised patients should not be vaccinated. HIV-positive patients who are asymptomatic may receive the vaccine.
Meningococcal Vaccine
The meningococcal vaccine is recommended for everyone at age 11 visit. It is also recom- mended for young adults living in dormitories or barracks, people exposed to outbreaks, those with asplenia or terminal complement deficiencies, those who travel to endemic regions (traveling to Mecca), and those exposed to Neisseria meningitidis.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
6
Chapter 1 ● Preventive Medicine
Human Papillomavirus (HPV) Vaccine
The human papillomavirus (HPV) vaccine is recommended for women age 9–26, regardless of sexual activity. It should not be administered in pregnancy. The regimen is in 3 doses: 0, 2, and 6 months.
Herpes Zoster Vaccine
The zoster vaccine is a live vaccine that has been shown to reduce the incidence of shingles by 50%. It has also been shown to reduce the number of cases of post-herpetic neuralgia, as well as the severity and duration of pain/discomfort associated with shingles. The vaccine is, basically, a larger-than-normal dose of the chicken pox vaccine, as both shingles and chicken- pox are caused by the same virus, varicella zoster virus (VZV).
The shingles vaccine (Zostavax), a live vaccine given as a single injection, is recommended for adults age ≥60, whether they have already had shingles or not. Some people report a chickenpox- like rash after receiving it. The vaccine should not be given to the following individuals:
Those with a weakened immune system due to HIV/AIDS or another disease that affects the immune system
Those who are receiving immune system-suppressing drugs or treatments, such as steroids, adalimumab (Humira), infliximab (Remicade), etanercept (Enbrel), radiation or chemotherapy
Those who have neoplasia, which affects the bone marrow or lymphatic system, such as leukemia or lymphoma
Clinical Recall
In which of the following patients will the vaccination have the greatest benefit?
Influenza vaccine in a 16-year-old asymptomatic high school student
Pneumococcal vaccination given to a 48-year-old male COPD patient
HBV vaccination given to a heart failure patient
Answer: D
SMOKING
A 25-year-old man comes to the clinic for evaluation of a stuffy nose and fever. Over the course of the interview, the patient states that he smokes 3 packs of cigarettes per day and has been doing so for the last 7 years.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
7
USMLE Step 2 l Internal Medicine
Note
Do not use varenicline in patients with a history of psychiatric disease.
Smoking is responsible for 1 in every 5 deaths in the United States. Smoking cessation is the most preventable cause of disease. Physicians can take the following steps to assist:
ASK about smoking at every visit.
ADVISE all smokers to quit at every visit.
ATTEMPT to identify those smokers willing to quit.
ASSIST the patient by setting a quit date (usually within 2 weeks) and using nicotine patches/gum, the oral antidepressant bupropion or varenicline as supportive therapy. Varenicline and bupropion are more effective than patches.
ARRANGE follow-up. If the quit attempt was successful, then provide positive reinforcement. If it was not successful, then determine why the patient smoked and elicit a recommitment to smoking cessation. Most patients require several attempts before being successful.
Monotherapy treatment for smoking cessation includes nicotine replacement therapy (trans- dermal nicotine patches, gum, lozenges, inhalers), bupropion, and varenicline.
Bupropion lowers the seizure threshold so do not use in cases of alcohol abuse.
Varenicline causes an increased rate of suicidal thoughts, so first screen for depression.
Place a follow-up call 1–2 weeks after quit date. The use of pharmacotherapy doubles the effect of any tobacco cessation intervention.
All women age >65 should be given DEXA bone density scan. Screening should begin at age 60 if there is low body weight or increased risk of fractures. A bone density test uses x-rays to measure how many grams of calcium and other bone minerals are packed into a segment of bone. The bones that are tested are in the spine, hip and forearm. Bone density test results are reported in 2 numbers: T-score and Z-score.
The T-score is the bone density compared with what is normally expected in a healthy young adult of the same sex. The T-score is the number of units—standard deviations—that bone density is above or below the average.
T-score >2.5 SD indicates the likelihood of osteoporosis and increased risk of fracture.
The diagnosis of osteoporosis by DEXA scan also means that treatment should be initiated with bisphosphonates, oral daily calcium supplementation, and vitamin D.
The Z-score is the number of standard deviations above or below what is normally expected for someone of the same age, sex, weight, and ethnic or racial origin.
Z-score ≤-2 may suggest that something other than aging is causing abnormal bone loss (consider drugs causing osteoporosis such as corticosteroids).
The goal in this case is to identify the underlying problem.
ABDOMINAL AORTIC ANEURYSM
U/S should be done once in men age >65 who have ever smoked. There are no screening recommendations for male nonsmokers and women, regardless of smoking history.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
8
Chapter 1 ● Preventive Medicine
HYPERTENSION, DIABETES MELLITUS, AND HYPERCHOLESTEROLEMIA
A 45-year-old man comes to the physician anxious about his health. Five years ago his mother was diagnosed with diabetes and high cholesterol. He is worried about his health and risk for heart disease. Physical examination is within normal limits.
Cholesterol screening should commence at age 35 in men who have no risk factors for coronary artery disease. In both men and women with risk factors, screening should be done routinely after age 20. Management should not be determined by an isolated reading because cholesterol levels may fluctuate between measurements. Repeat in 5 years in low-risk individuals.
Screening for diabetes mellitus should be considered only for patients with hypertension (>135/80 mm Hg). Diabetes mellitus is diagnosed in either of these situations:
Two fasting glucose measurements are >125 mg/dL, HbA1c >6.5%
Random glucose >200 mg/dL accompanied by symptoms
There is insufficient evidence for or against routine screening. The strongest indication is for those with hypertension and hyperlipidemia.
Screening is recommended for elevated blood pressure in those age >18, at every visit. Screen- ing is not recommended for carotid artery stenosis with duplex.
ALCOHOL ABUSE
Physicians should screen for alcohol abuse by using the CAGE questionnaire: Have you ever felt the need to: Cut down on your drinking?
Have you ever felt: Annoyed by criticism of your drinking?
Have you ever felt: Guilty about your drinking? Have you ever taken a morning: Eye opener?
A positive screen is 2 “yes” answers. One “yes” should raise the possibility of alcohol abuse.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
9
USMLE Step 2 l Internal Medicine
VIOLENCE AND INJURY
A 27-year-old woman presents to the emergency department complaining of right-arm pain. When asked how she sustained the injury, she states that she fell down the steps in front of her house. The patient appears anxious and nervous. On physical examination there are various 2 cm wide lacerations on her buttocks.
Injuries are the most common cause of death in those age <65. The role of the physician is to advise patients about safety practices that can prevent injury, e.g., using seat belts, wearing bicycle helmets, and not driving after drinking alcohol.
Identifying women who are at increased risk of physical or sexual abuse is an essential role for a physician. Simply asking them if they have been hit, kicked, or physically hurt can increase identification by >10%.
Which of the following is indicated in a 65-year-old male smoker?
Answer: E
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
10
EnCdhoacprtienroTloitglye #2
Learning Objectives
List presenting signs and therapeutic approaches to disease of the anterior pituitary, posterior pituitary, thyroid, parathyroid, and adrenal glands
Describe disorders that cause hypogonadism or affect the testes
DISEASES OF THE PITUITARY GLAND
The pituitary is surrounded by the sphenoid bone and covered by the sellar diaphragm, an extension from the dura mater. It lies in the sella turcica near the hypothalamus underneath the optic chiasm.
Neurohypophysis (or posterior lobe), the storage site for hormones produced by neurose- cretory neurons (supraoptic and paraventricular nuclei) within the hypothalamus: ADH (antidiuretic hormone or vasopressin) and oxytocin
There is a close relationship between the hypothalamus and the pituitary. The hypothalamus regulates the release of hormones from the anterior pituitary by different hypothalamic releasing and inhibiting hormones (hypothalamic–pituitary axis).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
11
USMLE Step 2 l Internal Medicine
Third ventricle
Hypothalamus
Optic
chiasm
Releases inhibiting hormones
Supraoptic
paraventricular
Nucleus
Posterior lobe (ADH oxytocin storage)
Stalk
As a sample summary, the hypothalamus secretes releasing factors for each respective pituitary stimulatory hormone. Each pituitary hormone stimulates release of the active hormone from the final target gland. The active hormones then inhibit release of releasing factors and stimula- tory hormones from the hypothalamus and pituitary gland, respectively. This is feedback inhibition, and it leads to a steady state of both respective hormones involved in the axis.
Clinically, note the following to screen and diagnose diseases:
Disease states involving overproduction of target hormones lead to suppressed levels
of pituitary hormones.
Disease states involving underproduction of target hormones lead to increased levels
of pituitary hormones.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
12
Chapter 2 ● Endocrinology
Hypothalamus
–
Releasing
factors
–
–
Pituitary
–
Stimulating
hormones
Target Glands
GH
Thyroid
Adrenal
Gonads
(ovarian, testes)
Liver
T4, T3
DISEASES OF THE ANTERIOR PITUITARY
Syndromes causing excess production of hormones usually arise from benign tumors of a sin- gle cell type.
Microadenomas (more common) are tumors <1 cm in diameter.
Macroadenomas (less common) are tumors >1 cm in diameter. Larger tumors can occasionally compress the optic chiasm and cause visual deficits.
Table 2-1. Pituitary Adenomas by Function
Prolactin | |
ACTH | 10–15% |
Gonadotroph | 10–15% |
Hyperprolactinemia
A 32-year-old woman sees her physician because she has noticed milk-like discharge from her breasts the past 4 weeks. She also states that she has not menstruated in 2 months. The examination reveals galactorrhea but is otherwise normal.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
13
USMLE Step 2 l Internal Medicine
Note
Cabergoline is used more often than bromocriptine because of a better side-effect profile. It is the preferred treatment for galactorrhea.
Excess prolactin secretion is a common clinical problem in women and causes the syndrome of galactorrhea-amenorrhea. The amenorrhea appears to be caused by inhibition of hypothalamic release of gonadotropin-releasing hormone (GnRH) with a decrease in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Prolactin inhibits the LH surge that causes ovulation. The LH/FSH-producing cells are not destroyed, just suppressed.
Although hyperprolactinemia is also seen in men, gynecomastia and especially galactorrhea are very rare. The most common presenting symptom in men is erectile dysfunction and decreased libido.
Hyperprolactinemia can be seen in natural physiologic states such as pregnancy, early nursing, hypoglycemia, seizure, exercise, stress, sleep, cirrhosis, nipple stimulation, and chronic renal failure (due to PRL clearance).
Autonomous production of prolactin occurs with pituitary adenomas; these so-called prolacti- nomas are the most common functioning pituitary adenomas, accounting for 60% of all pituitary tumors. They are usually microadenomas when they occur in women and macroad- enomas in men, usually presenting with visual field deficits, etc. Macroadenomas can obstruct the pituitary stalk, increasing prolactin release by blocking dopamine transport from hypo- thalamus (stalk effect). Other examples are tumors such as craniopharyngioma, meningioma, and dysgerminoma; empty sella; and trauma.
Hyperprolactinemia can also occur with decreased inhibitory action of dopamine. This occurs with the use of drugs that block dopamine synthesis (phenothiazines, metoclopramide) and dopamine-depleting agents (α-methyldopa, reserpine). Tricyclic antidepressants, narcotics, cocaine, SSRIs, and risperidone can also cause increased prolactin.
Stimuli that overcome the normal dopamine inhibition can also lead to hyperprolactinemia. An example of this is primary hypothyroidism (resulting in an increase in thyrotropin- releasing hormone [TRH]) and subsequently an increase in prolactin release.
Always check TSH in patients with elevated prolactin.
Clinical Presentation. Hyperprolactinemia presents with galactorrhea, menstrual abnormali- ties amenorrhea/oligomenorrhea, osteopenia and osteoporosis in long-standing cases, infertility, and gynecomastia in women; men present with hypogonadism, erectile dysfunction, decreased libido, gynecomastia, and infertility. Men typically do not develop galactorrhea.
Women are detected earlier because of menstrual symptoms. Hence, microadenomas are more common in women.
Diagnosis. Always exclude states such as pregnancy, lactation, hypothyroidism and medica- tions before starting the workup of hyperprolactinemia. Prolactinomas may co-secrete growth hormone (GH).
Prolactin >100 ng/mL suggests probable pituitary adenoma
Prolactin level should be commensurate with tumor size
Prolactin 100 ng/mL correlates with tumor approximately 1 cm
Prolactin 200 ng/mL correlates with tumor approximately 2 cm
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
14
Chapter 2 ● Endocrinology
Management. Treat initially with cabergoline or bromocriptine (a dopamine-agonist), which will reduce prolactin level in hyperprolactinemia. Dopamine normally inhibits prolactin release.
About 90% of patients treated with cabergoline have a drop in prolactin to <10% of pretreatment levels.
Reserve surgery only for those adenomas not responsive to cabergoline/bromocriptine or associated with significant compressive neurologic effects.
Surgery is more effective for microadenomas than macroadenomas (only 30% of macroadenomas can be successfully resected, with long-term recurrence >50%).
Use radiation therapy if drug therapy and surgery are ineffective at reducing tumor size and prolactin level.
Clinical Recall
Which of the following therapeutic options is most appropriate in the management of prolactinoma?
Somatostatin
Surgical resection
Radiation therapy
Cabergoline
Acromegaly
Acromegaly (called gigantism in children) is a syndrome of excessive secretion of growth hormone (GH). It is an insidious, chronic debilitating disease associated with bony and soft tissue overgrowth, and increased mortality.
Wikimedia, Philippe Chanson and Sylvie Salenave
Figure 2-3. Acromegaly Facial Features
Note
A basal, fasting, morning PRL
>100−200 mg/L (normal
<20 mg/L) in a nonpregnant woman indicates a need for a pituitary MRI.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
15
USMLE Step 2 l Internal Medicine
Note
The most common cause of death in acromegaly is cardiovascular mortality.
Acromegaly is caused by a pituitary adenoma (usually macroadenoma in 75% of the cases that produce GH). Rarely ectopic tumors can produce growth hormone-releasing hormone (GHRH) and cause this syndrome. Less than 1% are malignant. GH is produced by 20% of pituitary tumors.
Clinical Findings. GH excess occurs most frequently around decades 3–5. The following findings may be seen.
Various skeletal and soft tissue changes
Enlargement of the hands and feet, coarsening of facial features, and thickened skin folds; increase in shoe, hat, glove, and ring size
Enlarged nose and mandible (prognathism and separation of teeth), sometimes causing underbite
Deeper voice
Increased sweating
Enlarged internal organs, including heart, lung, spleen, liver, and kidneys
Interstitial edema, osteoarthritis, and entrapment neuropathy (carpal tunnel syn- drome)
Menstrual problems (common) due to co-secretion of prolactin by GH-producing tumor
Cardiac anomalies (10–20%) such as hypertension, arrhythmia, hypertrophic cardio- myopathy, and accelerated atherosclerosis
Metabolic changes, i.e., impaired glucose tolerance (80%) and diabetes (13–20%)
Proliferated articular cartilage, causing severe joint disease
Diagnosis. Patients with acromegaly have symptoms for ~9 years before the diagnosis is made. The best initial test is IGF-1 level, which is significantly elevated. The confirmatory test is GH measurement after 100 g of glucose is given orally; if GH remains high (>5 ng/mL), it is positive and suggests acromegaly. Normally, glucose load should completely suppress levels of GH.
Measurement of insulin-like growth factor (IGF) or somatomedin correlates with disease activity. Radiologic studies such as MTI and CT are used to localize the tumor but should be done only
after GH excess is documented biochemically. MRI is superior to CT in that it will show a tumor in 90% of people with acromegaly.
Management. The objectives are to decrease GH levels to normal, stabilize or decrease tumor size, and preserve normal pituitary function. Transsphenoidal surgery provides a rapid response. Hypopituitarism can result in 10–20%. Primary treatment is surgery.
Somatostatin analogues are the drugs of choice. Octreotide and lanreotide reduce GH values (70% of patients) and cause partial tumor regression (20–50% of patients). Octreotide is the best medical therapy for acromegaly. The main side effect of concern with somatostatin analogues is cholestasis, leading to cholecystitis.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
16
Chapter 2 ● Endocrinology
Dopamine-agonists such as bromocriptine and cabergoline are used if surgery is not curative, with 10% of patients responding to these drugs.
Pegvisomant is a growth hormone analogue which antagonizes endogenic GH by blocking peripheral GH binding to its receptor in the liver. Important to note, pegvisomant is a second-line agent.
Radiotherapy, used only if surgery and drug therapy do not work, results in slow resolution of disease and hypopituitarism in 20% of patients.
Complications of acromegaly can arise from pressure of the tumor on the surrounding structures or invasion of the tumor into the brain or sinuses. Other complications include cardiac failure (most common cause of death in acromegaly), diabetes mellitus, cord com- pression, and visual field defects.
Hypopituitarism
Hypopituitarism is partial or complete loss of anterior function that results from any lesion which destroys the pituitary or hypothalamus or which interferes with the delivery of releasing and inhibiting factors to the anterior hypothalamus. GH and gonadotropins (FSH, LH) are typically lost early.
Large pituitary tumors, or cysts, as well as hypothalamic tumors (craniopharyngiomas, meningiomas, gliomas) can lead to hypopituitarism. Pituitary adenomas are the most common cause of panhypopituitarism; the mass compresses the gland, causing pressure, trauma, and necrosis.
Pituitary apoplexy is a syndrome associated with acute hemorrhagic infarction of a preexisting pituitary adenoma and manifests as severe headache, nausea or vomiting, and depression of consciousness. It is a medical and neurosurgical emergency.
Inflammatory diseases can lead to hypopituitarism: granulomatous diseases (sarcoidosis, tuberculosis [TB], syphilis), eosinophilic granuloma, and autoimmune lymphocytic hypo- physitis (usually associated with other autoimmune diseases such as Hashimoto thyroiditis and gastric atrophy). Trauma, radiation, surgery, infections, and hypoxia may also damage both the pituitary and hypothalamus.
Vascular diseases such as Sheehan postpartum necrosis (initial sign being the inability to lactate) and infiltrative diseases including hemochromatosis and amyloidosis may induce this state as well.
Stroke can also damage these cells. Stroke can cause central diabetes insipidus due to damage of hypothalamus and/or posterior pituitary.
Clinical Findings. The following hormones appear in the order in which they are lost in hypopituitarism.
Gonadotropin deficiency (LH and FSH) can occur in women and lead to amenorrhea, genital atrophy, infertility, decreased libido, and loss of axillary and pubic hair.
In men, decreased LH and FSH results in impotence, testicular atrophy, infertility, decreased libido, and loss of axillary and pubic hair.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
17
USMLE Step 2 l Internal Medicine
GH deficiency occurs next and is not clinically detectable in adults, though it may manifest as fine wrinkles and increased sensitivity to insulin (hypoglycemia). GH deficiency gives an asymptomatic increase in lipid levels and a decrease in muscle, bone, and heart mass. It also may accelerate atherosclerosis, and it increases visceral obesity.
GH deficiency in children results in growth failure and short stature.
Thyrotropin (TSH) deficiency results in hypothyroidism with fatigue, weakness, hyperlipidemia, cold intolerance, and puffy skin without goiter.
Adrenocorticotropin (ACTH) deficiency occurs last and results in secondary adrenal insufficiency caused by pituitary disease.
There is decreased cortisol, which results in fatigue, decreased appetite, weight loss, decreased skin and nipple pigment, and decreased response to stress (as well as fever, hypotension, and hyponatremia).
Electrolyte changes like hyperkalemia and salt loss are minimal in secondary adrenal insuffi- ciency because aldosterone production is mainly dependent on the renin-angiotensin system. ACTH deficiency does not result in the salt wasting, hyperkalemia, and death that are associ- ated with aldosterone deficiency.
Diagnosis. The first step in diagnosing pituitary insufficiency is to measure GH, TSH, LH, and IGF-1. The most reliable stimulus for GH secretion is insulin-induced hypoglycemia. After injecting 0.1 μ/kg of regular insulin, blood glucose declines to <40 mg/dL; in normal conditions that will stimulate GH levels to >10 mg/L and exclude GH deficiency. Random GH and IGF levels are not sensitive enough to diagnose GH deficiency. This is why a provocative test is used.
Arginine infusion can also stimulate growth hormone release. Measure GH levels after infusing arginine. This is less dangerous because it does not lead to hypoglycemia.
To diagnose ACTH deficiency, basal cortisol levels may be preserved (the problem could
be only in response to stress). Insulin tolerance test is diagnostic and involves giving 0.05–0.1 U/kg of regular insulin and measuring serum cortisol; plasma cortisol should increase to >19 mg/dL. Metyrapone tests for decreased ACTH production. Metyrapone blocks cortisol production, which should increase ACTH levels. A failure of ACTH levels to rise after giving metyrapone would indicate pituitary insufficiency. Cosyntropin (ACTH) stimulation may give abnormally low cortisol output if pituitary insufficiency has led to adrenal atrophy.
To diagnose gonadotropin deficiency in women, measure LH, FSH, and estrogen. In males, measure LH, FSH, and testosterone. To diagnose TSH deficiency, measure serum thyroxine (T4) and free triiodothyronine (T3), which are low, with a normal to low TSH.
Management. Management of hypopituitarism involves treating the underlying causes. Multiple hormones must be replaced, but the most important is cortisol.
Empty Sella Syndrome (ESS)
ESS is in the differential diagnosis of enlarged sella caused by pituitary tumors. In ESS, the sella has no bony erosion. It is caused by herniation of the suprasellar subarachnoid space through an incomplete diaphragm sella. No pituitary gland is visible on CT or MRI. The syndrome can be primary (idiopathic) and is also associated with head trauma and radiation therapy. Most patients with these syndromes are obese, multiparous women with headaches; 30% will have hypertension. Endocrine symptoms are absent. Therapy is reassurance.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
18
Chapter 2 ● Endocrinology
Normal
Empty Sella
Pia
CSF
Arachnoid CSF
Arachnoid
dura
Arachnoid dura
Diaphragma sella
Pia
Basilar cisterns CSF
Figure 2-4. Empty Sella Syndrome
Clinical Recall
What is the best initial test to diagnose acromegaly?
MRI of the brain
Pituitary biopsy
DISEASES OF THE POSTERIOR PITUITARY
Vasopressin (or antidiuretic hormone [ADH]) and oxytocin are synthesized in neurons of the supraoptic and paraventricular nuclei in the hypothalamus, then transported to the posterior pituitary lobe to be released into the circulatory system. A deficiency of ADH will cause dia- betes insipidus (DI), while an excess of ADH will cause syndrome of inappropriate secre- tion of ADH (SIADH).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
19
USMLE Step 2 l Internal Medicine
Diabetes Insipidus
Diabetes insipidus (DI) often starts in childhood or early adult life. Men > women.
Central diabetes insipidus (CDI) is a disorder of the neurohypophyseal system, caused by partial or total deficiency of ADH.
Results in excessive, dilute urine and increased thirst associated with hypernatremia
Causes include neoplastic or infiltrative lesions of the hypothalamus or pituitary (60% also have partial or complete loss of anterior pituitary function); in the hypothalamus these lesions can be secondary to adenoma, craniopharyngioma, etc.; in the pituitary gland, adenoma, leukemia, or sarcoid histocytosis can lead to DI
Other causes include pituitary or hypothalamic surgery, radiotherapy, severe head injuries, anoxia, hypertension, meningitis
Encephalitis, TB, and syphilis may affect the pituitary as well.
Nephrogenic diabetes insipidus (NDI) is caused by renal resistance to the action of vasopressin. It can be idiopathic or it can be secondary to hypercalcemia, hypokale- mia, sickle cell disease, amyloidosis, myeloma, pyelonephritis, sarcoidosis, or Sjögren syndrome.
Causes include drugs (lithium, demeclocycline, colchicine)
Clinical Findings. Clinical findings of DI include polyuria, excessive thirst, polydipsia (16–20 L/d), hypernatremia with high serum osmolarity and coexisting low urine osmolarity and urine specific gravity <1.010. Nocturia is expected.
Hypertonicity is not usually present if the patient has an intact thirst mechanism and can increase water intake to keep up with urinary loss.
1000
800
600
400
200
0
Posm
Figure 2-5. Posm versus Uosm during Dehydration in Normal Subjects
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
20
Chapter 2 ● Endocrinology
Diagnosis. The water deprivation test compares Uosm after dehydration versus Uosm after vasopressin.
In a normal person, the response to fluid restriction is decreased urine volume and increased urine osmolality.
In DI, urine volume remains increased despite volume depletion.
ADH will be decreased in central DI and increased in nephrogenic DI. If a patient falls to the right of the shaded area, the diagnosis is DI.
Giving ADH
Urine volume
NDI
Figure 2-6. Water Restriction Test
The differential diagnosis of DI includes primary disorders of water intake (psychogenic polydipsia, drug-induced polydipsia from chlorpromazine, anticholinergic drugs, or thiorida- zine) and hypothalamic diseases.
Management. Management for CDI includes the following:
Hormone replacement with vasopressin subcutaneously or desmopressin subcutane- ously, orally, or intranasally
Drugs to stimulate the secretion of ADH or increase release (chlorpropamide, clofi- brate, or carbamazepine)
HCTZ or amiloride (for NDI) to enhance the reabsorption of fluid from proximal tubule
Chlorthalidone
Correction of any calcium and/or potassium abnormalities
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
21
USMLE Step 2 l Internal Medicine
Syndromes Associated with Vasopressin (ADH) Excess
Syndromes associated with ADH excess involve a mechanism of defense against hypovolemia or hypotension. This includes adrenal insufficiency, excessive fluid loss, fluid deprivation, and probably positive-pressure respiration.
Excessive release of ADH from the neurohypophysis is associated with drugs or diseases (SIADH).
Syndrome of Inappropriate Antidiuretic Hormone
Syndrome of inappropriate antidiuretic hormone (SIADH) has many causes:
Malignancy such as small cell carcinoma, carcinoma of the pancreas, and ectopic ADH secretion
Nonmalignant pulmonary disease such as tuberculosis, pneumonia, and lung abscess
CNS disorder such as head injury, cerebral vascular accident, and encephalitis
Drugs such as chlorpropamide, clofibrate, vincristine, vinblastine, cyclophosphamide, and carbamazepine
In general, increased ADH causes water retention and extracellular fluid volume expansion without edema or hypertension, owing to natriuresis. The water retention and sodium loss both cause hyponatremia, which is a key feature in SIADH. Hyponatremia and concentrated urine (Uosm > 300 mOsm) are seen, as well as no signs of edema or dehydration. When
hyponatremia is severe (sodium <120 mOsm), or acute in onset, symptoms of cerebral edema
become prominent (irritability, confusion, seizures, and coma).
Urine sodium concentration >20 mEq/L (inappropriate natriuresis)
Low blood urea nitrate (BUN), low creatinine, low serum uric acid, and low albumin
Management. Treat underlying causes. Restrict fluid to 800–1,000 mL/d to increase serum sodium (in chronic situations when fluid restriction is difficult to maintain, use demeclocy- cline which inhibits ADH action at the collecting duct [V2]). Conivaptan and tolvaptan are V2 receptor blockers indicated for moderate to severe SIADH. For very symptomatic patients (severe confusion, convulsions, or coma), use IV hypertonic saline (3%) 200–300 mL in 3–4 h. The rate of correction should be 0.5–1 mmol/L/h serum Na.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
22
Chapter 2 ● Endocrinology
Clinical Recall
Which of the following laboratory findings is suggestive of central diabetes insipidus?
Increased serum osmolarity, decreased urine osmolarity, decreased ADH
Decreased serum osmolarity, increased urine osmolarity, increased ADH
Increased serum osmolarity, decreased urine osmolarity, increased ADH
Increased serum osmolarity, increased urine osmolarity, increased ADH
Decreased serum osmolarity, decreased urine osmolarity, decreased ADH
The normal function of the thyroid gland is directed toward the secretion of l-thyroxine (T4) and l-3,5,5′-triiodothyronine (T3), which influence a diversity of metabolic processes.
Diseases of the thyroid can be quantitative or qualitative alterations in hormone secretion, enlargement of thyroid (goiter), or both.
Generalized enlargement can be associated with increased, normal, or decreased function of the gland, depending on the underlying cause.
Focal enlargement of the thyroid can be associated with tumors (benign or malignant).
The most sensitive test in thyroid diseases is the TSH. If TSH is normal, then the patient is euthyroid.
Total T4 and T3, however, does not always reflect actual thyroid function.
Increased TBG levels are seen in pregnancy and the use of oral contraceptives. Total T4 will increase but free or active T4 level will be normal.
Decreased TBG levels are seen in nephrotic syndrome and the use of androgens. Total T4 will decrease but free or active T4 will be normal, with the patient being euthyroid.
Clinical Pearl
Always check free T4 to assess thyroid function.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
23
USMLE Step 2 l Internal Medicine
Hypothalamus
Anterior Pituitary
TRH
+
+
–
TSH
+
Thyroid
Proteases
I–: inorganic iodide IPO: iodide peroxidase MIT: monoiodotyrosine DIT: di-iodotyrosine
Figure 2-7. Pathways for Synthesis and Secretion of Thyroid Hormones
RAIU (thyroid-reactive iodine uptake) varies directly with the functional state of the thyroid. After 24 hours, normal uptake is 5–30% of administered dose. RAIU is increased in Graves’ disease or toxic nodule and decreased in thyroiditis or surreptitious ingestion of thyroid hormone.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
24
Chapter 2 ● Endocrinology
Table 2-2. Evaluating Thyroid Function
Thyroid Hormones and TSH | RAI Uptake Scan | Diagnosis |
Increased RAIU | De novo synthesis of hormone (primary hyperthyroidism) | |
Decreased RAIU | Factitious hyperthyroidism or inflammation/destruction of the gland releasing preformed hormone into the circulation (subacute thyroiditis) | |
Decreased RAIU | Secondary or tertiary hypothyroidism |
Decreased TSH
Free increased T4; increased T3
Decreased TSH
Free increased T4; increased T3
Decreased TSH
Free decreased T4; decreased T3
Other tests include antimicrosomal and antithyroglobulin antibodies, which are detected in Hashimoto thyroiditis. In Graves’ disease, thyroid-stimulating immunoglobulin (TSI) is found.
Serum thyroglobulin concentration can be used to assess the adequacy of treatment and follow-up of thyroid cancer, and to confirm the diagnosis of thyrotoxicosis factitia.
Hyperthyroidism (Thyrotoxicosis)
A wide range of conditions can cause hyperthyroidism, although Graves’ disease is the most common. Graves’, an autoimmune disorder, causes the production of antibodies (thyroid stimulating immunoglobulin [TSI]), which stimulate the thyroid to secrete T4 and T3.
Toxic multinodular goiter (Plummer disease), a non-autoimmune disease of the elderly associated commonly with arrhythmia and CHF
Simple goiter
Transient hyperthyroidism results from subacute thyroiditis (painful) or lymphocytic thyroid- itis (painless, postpartum).
Drugs such as amiodarone, alpha interferon, and lithium can induce thyrotoxicosis. Excess iodine, as may occur in people taking certain expectorants or iodine-containing contrast agents for imaging studies, may cause hyperthyroidism. Extrathyroid source of hormones include thyrotoxi- cosis factitia and ectopic thyroid tissue (struma ovarii, functioning follicular carcinoma). Rarely, hyperthyroidism can result from excess production of TSH (secondary hyperthyroidism).
Clinical Pearl
Physical Exam: Hyperthyroid Patient Painless & diffuse enlargement = Graves’
Painful & diffuse enlargement =
subacute thyroiditis
Painless & nodules = Plummer
No thyroid enlargement or thyroid not palpated = factitious
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
25
USMLE Step 2 l Internal Medicine
Note
For treatment purposes, it is important to distinguish primary hyperthyroidism (Graves’ disease or toxic adenoma) from thyroiditis .
Courtesy of Tom D. Thacher, MD
Figure 2-8. Pretibial Myxedema, a Manifestation of Graves’ Disease
Graves’ disease (toxic diffuse goiter) is hyperthyroidism with diffuse goiter, exophthalmos, and dermopathy. In Graves’, autoantibodies form and bind to the TSH receptor in thyroid cell membranes, stimulating the gland to hyperfunction (TSI).
Significant genetic component, i.e., a person is more likely to be affected if they have family member with the disease
Patients with another autoimmune disease such as type 1 diabetes or pernicious anemia are more likely to be affected
Smoking causes increased risk of disease and may make the exophthalmos worse
Wikimedia, Jonathan Trobe, MD/University of Michigan Kellogg Eye Center
Figure 2-9. Proptosis and Lid Retraction from Graves’ Disease
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
26
Chapter 2 ● Endocrinology
Clinical Findings. Graves’ is associated clinically with diffuse painless enlargement of the thyroid. Additionally:
Nervous symptoms (younger patients)
Cardiovascular and myopathic symptoms (older patients)
Atrial fibrillation
Emotional lability, inability to sleep, tremors
Frequent bowel movements
Excessive sweating and heat intolerance
Weight loss (despite increased appetite) and loss of strength
Proximal muscle weakness (prominent symptom in many patients, and the primary reason why they see a physician)
Warm and moist skin
Palmar erythema, along with fine and silky hair in hyperthyroidism
Ocular signs such as staring, infrequent blinking, and lid lag
Osteoporosis and hypercalcemia, as a result of increases in osteoclast activity
Diagnosis of Graves’ is made on history and physical exam. Lab studies include the following:
Decreased TSH (but elevated TSH in secondary hyperthyroidism)
Elevated RAIU (but decreased RAIU in subacute thyroiditis and factitious hyperthyroidism)
Elevated TSI, antithyroglobulin, and antimicrosomal antibodies
Treatment involves relief of symptoms and correction of the thyrotoxic state. Treat adrenergic hyperfunction with beta-adrenergic blockade (propranolol). Correct the high thyroid hor- mone levels with an anti-thyroid medication (methimazole or propylthiouracil), which blocks the synthesis of thyroid hormones and/or by treatment with radioactive iodine.
Methimazole has a longer half-life, reverses hyperthyroidism more quickly, and has fewer side effects than propylthiouracil.
Methimazole requires an average of 6 weeks to lower T4 levels to normal and is often given before radioactive iodine treatment; it can be taken 1x/ day.
Use propylthiouracil only when methimazole is not appropriate because of its poten- tial for liver damage; it must be taken 2−3x/ day.
For years propylthiouracil was the traditional drug of choice during pregnancy because it causes fewer severe birth defects than methimazole. However, experts now recommend that propylthiouracil be given during the first trimester only. This is because there have been rare cases of liver damage in people taking propylthiouracil. After the first trimester, women should switch to methimazole for the rest of the pregnancy.
For women who are nursing, methimazole is probably a better choice than propylthiouracil (to avoid liver side effects). Both drugs can cause agranulocytosis.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
27
USMLE Step 2 l Internal Medicine
Clinical Pearl
When large quantities of iodide are ingested by patients with hyperthyroidism, the result is thyroid hormone suppression (Wolff-Chaikoff effect).
The most commonly used ‘permanent’ therapy for Graves’ disease is radioactive iodine. Indications for its use (overusing antithyroid agents alone) include:
Large thyroid gland
Multiple symptoms of thyrotoxicosis
High levels of thyroxine
High titers of TSI
Because of the high relapse rate (>50%) associated with antithyroid therapy, many physicians in the United States prefer to use radioactive iodine as first-line therapy. Patients currently taking antithyroid drugs must discontinue the medication at least 2 days prior to taking the radiophar- maceutical since pretreatment with antithyroid drugs reduces the cure rate of radioiodine therapy in hyperthyroid diseases. With radioactive iodine, the desired result is hypothyroidism due to destruction of the gland, which usually occurs 2–3 months post-administration, after which hormone replacement treatment is indicated.
Subtotal thyroidectomy (and rarely total thyroidectomy) is indicated only in pregnancy (second trimester), in children, and in cases when the thyroid is so large that there are com- pressive symptoms.
Thyroid storm is an extreme form of thyrotoxicosis and an endocrine emergency. It is precipitated by stress, infection, surgery, or trauma. It manifests with extreme irritability, delirium, coma, tachycardia, restlessness, vomiting, jaundice, diarrhea, hypertension, dehydra- tion, and high fever.
Treatment involves supportive therapy with saline and glucose hydration, glucocorticoids, and oxygen cooling blanket. Therapy for hyperthyroidism is also used:
Follow with adrenergic antagonists (e.g., β-adrenergic blockers).
Stop the antithyroid drugs 1–2 weeks before and after the RAI treatment, as they block the uptake of the radioactive iodine.
Hypothyroidism
The far majority of hypothyroidism has a thyroid etiology (primary).
Secondary to chronic thyroiditis (Hashimoto disease) (most common cause of goitrous hypothyroidism; associated with antimicrosomal antibodies)
Postablative surgery or radioactive iodine, heritable biosynthetic defects, and iodine deficiency
Drugs such as lithium and acetylsalicylic acid
Amiodarone, interferon, and sulfonamides
Suprathyroid causes of hypothyroidism include pituitary induced (secondary hypothyroidism) or hypothalamic induced (tertiary hypothyroidism).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
28
Chapter 2 ● Endocrinology
Amiodarone, an antiarrhythmic drug used to treat ventricular and supraventricular tachyar- rhythmia, is structurally similar to T4 and contains approximately 40% iodine. Its other char- acteristics include:
Highly lipid-soluble and concentrated in the adipose tissue, muscle, liver, lung, and thyroid gland
High elimination half-life (50−100 days) so total body iodine stores can remain increased for up to 9 months after discontinuation of the drug
Thyroid abnormalities are seen in up to 20% of patients receiving long-term amioda- rone therapy. (However, other research has shown that with lower doses of amioda- rone, incidence of thyroid dysfunction is around 4%.)
The effects range from abnormal thyroid function test findings (without clinical hyper- or hypothyroidism) to overt thyroid dysfunction, which may be amioda- rone-induced thyrotoxicosis or amiodarone-induced hypothyroidism (both can develop in apparently normal thyroid glands or in glands with preexisting abnor- malities).
Type 1 occurs in patients with underlying thyroid pathology, e.g., autonomous nodular goiter or Graves’. Treatment is anti-thyroid therapy.
Type 2 is a result of amiodarone causing a subacute thyroiditis, with release of preformed thyroid hormones into the circulation. Treatment is glucocorticoids.
Amiodarone-induced hypothyroidism is due to inhibition of peripheral conversion of T4 to T3.
Clinical Findings.
In the newborn, cretinism (in 1/5,000 neonates) and juvenile hypothyroidism; persistent physiologic jaundice, hoarse cry, constipation, somnolence, and feeding problems
In later months, delayed milestones and dwarfism, coarse features, protruding tongue, broad flat nose, widely set eyes, sparse hair, dry skin, protuberant abdomen, potbelly with umbilical hernia, impaired mental development, retarded bone age, and delayed dentition
In the adult, there are stages:
Early stages may include lethargy; constipation; cold intolerance; stiffness/cramp- ing of muscles; carpal tunnel syndrome; menorrhagia
Later stages may include slowing intellectual and motor activity; decreased appe- tite; weight gain, dry hair/skin, deeper, hoarse voice; deafness
Elevated cholesterol and slow, deep tendon reflexes
Possible hyponatremia and anemia
Ultimately, myxedema (expressionless face, sparse hair, periorbital puffiness, large tongue, and pale, cool skin that feels rough and doughy)
Diagnosis of hypothyroidism is made by symptoms and physical findings. Lab tests confirm diagnosis.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
29
USMLE Step 2 l Internal Medicine
Clinical Pearl
Hashimoto thyroiditis presents more commonly as hypothyroidism.
Subacute (de Quervain) thyroiditis presents more commonly as hyperthyroidism.
Table 2-3. Confirmation of Hypothyroid Diagnosis*
Primary Hypothyroidism | 2° or 3° Hypothyroidism |
↑ TSH | Normal or ↓ TSH |
↓ T4, ↓ FT4 | ↓ T4, ↓ FT4 |
T3 decreases in lesser extent | Accompanied by decreased secretion of other hormones |
*Also seen: hypercholesterolemia, elevation of CPK, AST, hyponatremia, LDH; 12% associated with pernicious anemia
Management. The goal with hypothyroidism is to restore the metabolic state with levothyrox- ine. This should be done gradually in the elderly and those with coronary artery disease.
Levothyroxine (T4) should be administered with monitoring of TSH/T3, T4 levels (it takes 6 weeks after dosing changes for TSH to equilibrate).
In patients with suprathyroid hypothyroidism, T4 level rather than TSH is used to guide treatment.
If a patient has coronary heart disease that needs intervention, do the intervention (CABG or stent placement) before thyroid hormone replacement is initiated.
During pregnancy, demand for thyroid hormones may increase and thus close monitoring of TSH and T4 should be done. Hypothyroidism during pregnancy should be treated with levothyroxine, with serum TSH goal to be kept in the lower reference range. Serum TSH should be measured at 4−6 weeks’ gestation, then every 4−6 weeks until 20 weeks’ gestation.
Myxedema coma can result if severe, long-standing hypothyroidism is left untreated. Patients develop a hypothermic, stuporous state that is frequently fatal. It is associated with respiratory depression (CO2 retention). Myxedema coma is precipitated by cold exposure, trauma,
infections, and CNS depressants. Treatment includes very high doses of T4 along with T3.
Thyroiditis
Thyroiditis includes disorders of different etiologies characterized by inflammation of the thyroid. Each has a different clinical course and can be associated at one time or another with euthyroid, thyrotoxic, or hypothyroid state.
Subacute thyroiditis includes granulomatous, giant cell, or de Quervain thyroiditis. This can occur at any age, although most commonly in decades 4 and 5.
Likely of viral origin
Follows upper respiratory infection symptoms, e.g., malaise, fever, pain over the thyroid, and pain referred to the lower jaw, ears, neck, or arms
Thyroid gland is enlarged and firm
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
30
Chapter 2 ● Endocrinology
Lab findings include elevated erythrocyte sedimentation rate, decreased radioactive iodine uptake, initial elevation in T4 and T3 (due to leak of hormone from the gland) followed by hypothyroidism as the hormone is depleted
Differential diagnosis includes mostly Graves’ disease
Treatment is symptomatic with NSAIDs, prednisone, and propranolol. The disorder may smolder for months but eventually subsides with return to normal function.
Hashimoto thyroiditis is a chronic inflammatory process of the thyroid with lymphocytic infiltration of the gland. It is most often seen in middle-aged women, and is the most com- mon cause of sporadic goiter in children.
Likely caused by autoimmune factors, as evidenced by lymphocytic infiltration, increased immunoglobulin, and antibodies against components of thyroid tissue (antithyroglobulin Abs)
Main feature is a goiter that is painless; goiter is rubbery and not always symmetric
Diagnosis is suggested by finding a firm, nontoxic goiter on examination
Lab findings include metabolically normal values in early stages, then increased TSH and decreased T3 and T4.
High titers of antithyroid antibodies, namely antimicrosomal antibodies, are found, as are antithyroperoxidase antibodies
Histologic confirmation is made by needle biopsy (usually not needed) Treatment is L-thyroxine replacement.
Lymphocytic (silent, painless, or postpartum) thyroiditis is a self-limiting episode of thyro- toxicosis associated with chronic lymphocytic thyroiditis. It is common in women of any age.
Thyroid is nontender, firm, symmetric, and slightly/moderately enlarged
Lab findings include elevated T3/T4, low RAIU, and normal ESR; if antithyroid antibodies are present, they are only in low titer
This disease may last for 2–5 months and be recurrent (as in postpartum thyroiditis). Treat- ment is symptomatic with propranolol.
Reidel thyroiditis results from intense fibrosis of the thyroid and surrounding structures (including mediastinal and retroperitoneal fibrosis).
Neoplasia of the Thyroid
Thyroid adenomas may be nonfunctioning or hyperfunctioning. They are slow-growing over many years.
Thyroid adenomas can be follicular (most common; highly differentiated, autonomous nodule), papillary, or Hürthle.
Management for hyperfunctioning adenoma includes ablation with radioactive iodine.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
31
USMLE Step 2 l Internal Medicine
Clinical Pearl
RET mutations are the mutations associated with MEN2 and familial medullary thyroid carcinomas.
Follicular carcinoma (15–20% of all thyroid cancers) is common in the elderly. Women > men.
More malignant than papillary carcinoma
Spreads hematogenously with distant metastasis to the lung and bone
Treatment requires near total thyroidectomy with postoperative radioiodine ablation
Papillary carcinoma is the most common thyroid cancer (60–70% of all thyroid cancers are papillary). It is associated with history of radiation exposure.
Women > men by 2–3x
Bimodal frequency
Peaks occur in decades 2 and 3, and then again later in life
Slow-growing; spreads via lymphatics after many years
Treatment is surgery (small tumors limited to single area of thyroid) and surgery plus radia- tion (large tumors). TSH suppression therapy with levothyroxine is also used.
Anaplastic carcinoma (1–2% of all thyroid cancer) is seen primarily in elderly patients. Women > men. It is highly malignant with rapid and painful enlargement; 80% of patients die within 1 year of diagnosis. This cancer spreads by direct extension.
Medullary carcinoma (5% of all thyroid cancer) occurs as a sporadic form or familial form. It arises from parafollicular cells of the thyroid.
Often produces calcitonin (is the only thyroid cancer with elevated calcitonin)
Is the component of 2 types of MEN (multiple endocrine neoplasia)
In MEN type IIa (Sipple syndrome), pheochromocytoma, medullary thyroid carcinoma, and (in 50% of cases) parathyroid hyperplasia occur.
In MEN type IIb, pheochromocytoma, medullary carcinoma, and neuromas occur.
May occur in families without other associated endocrine dysfunctions
Calcitonin levels can also be increased from cancer of the lung, pancreas, breast, and colon
The only effective treatment is thyroidectomy.
Thyroid carcinoma should be suspected with the following:
Recent growth of thyroid or mass with no tenderness or hoarseness
History of radiation to the head, neck, or upper mediastinum in childhood (~30 years to develop thyroid cancer)
Presence of a solitary nodule or calcitonin production
Calcifications on x-ray such as psammoma bodies suggest papillary carcinoma; increased density is seen in medullary carcinoma. Do thyroid function tests first; cancer is never hyperfunctioning.
Evaluation of a solitary nonfunctioning nodule is done with fine-needle aspiration (FNA) for cytology for most patients. Five percent of nonfunctioning thyroid nodules prove to be malignant; functioning nodules are very seldom malignant.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
32
Chapter 2 ● Endocrinology
The first test to do in a patient with a thyroid nodule is TSH; if that is normal, then proceed to FNA. U/S is useful to distinguish cysts from solid nodules.
Clinical Recall
Which of the following is the best initial step (most sensitive test) for the
diagnosis of a patient suspected of having hyperthyroidism?
RAIU scan
Free T4 level
Free T3 level
TSH level
The function of parathyroid hormone (PTH) is to maintain extracellular fluid calcium con- centration.
Acts directly on the bone and kidney, and indirectly on intestine (through its effects on synthesis of 1,25-dihydroxycholecalciferol [1,25(OH)2D3]) to increase serum calcium
Is closely regulated by the concentration of serum-ionized calcium
Inhibits phosphate reabsorption in the kidney tubule, also favoring bone dissolution and calcium release from bones
Activates vitamin D, which increases the GI absorption of calcium
Calcium regulation involves 3 tissues (bone, kidney, and intestine) and 3 hormones (PTH (hypercalcemic), calcitonin (hypocalcemic), and activated vitamin D (hypercalcemic)).
Hypercalcemia
Hypercalcemia represents an increase in the total or free calcium level. About 98% of calcium is stored in bone. Calcium is absorbed from the proximal portion of the small intestine, particularly the duodenum. About 80% of an ingested calcium load in the diet is lost in the feces, unabsorbed.
Of the 2% of calcium that is circulating in blood, free calcium is 50%, protein bound is 40%, with only 10% bound to citrate or phosphate buffers.
The most common cause of hypercalcemia is primary hyperparathyroidism; it is usually asymptomatic and is found as a result of routine testing. Hypercalcemia due to malignancy is caused by a PTH-like protein produced by squamous cell carcinoma of the lung or metastatic disease to the bone. Granulomatous diseases such as sarcoidosis, tuberculosis, berylliosis, histoplasmosis, and coccidioidomycosis are all associated with hypercalcemia. Neutrophils in
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
33
USMLE Step 2 l Internal Medicine
granulomas have their own 25-vitamin D hydroxylation, producing active 1,25 vitamin D. Rare causes include vitamin D intoxication, thiazide diuretics, lithium use, and Paget disease, as well as prolonged immobilization. Hyperthyroidism is associated with hypercalcemia because there is a partial effect of thyroid hormone on osteoclasts. Acidosis results in an increased amount of free calcium. This is because albumin buffers acidosis. Increased binding of hydrogen ions to albumin results in the displacement of calcium from albumin.
Familial hypocalciuric hypercalcemia (FHH) is a benign form of hypercalcemia. It presents with mild hypercalcemia, family history of hypercalcemia, urine calcium to creatinine ratio
<0.01, and urine calcium <200 mg/day (hypocalciuria). Most cases are associated with loss of function mutations in the CaSR gene, which encodes a calcium sensing receptor (expressed in kidney and parathyroid tissue). The perceived lack of calcium levels by the parathyroid leads to high levels of parathyroid hormone. FHH is indicated by the presence of hypercalcemia at the same time with hypocalciuria. (In all other causes of hypercalcemia, elevated calcium levels in the blood are correlated with elevated calcium urine levels, as a properly sensing kidney works to excrete calcium.) No treatment is generally required, since patients are most commonly asymptomatic.
Neurologic: decreased mental activity such as lethargy and confusion
GI: decreased bowel activity such as constipation and anorexia but also possible nausea and vomiting; pancreatitis due to precipitation of calcium in the pancreas (severe pancreatitis, however, is associated with hypocalcemia because of binding of calcium to malabsorbed fat in the intestine)
Renal: polyuria and polydipsia due induction of NDI; calcium precipitation in the kidney, causing kidney stones and nephrolithiasis
Cardiovascular: hypertension (30–50% of patients); EKG will show a short QT
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
34
Chapter 2 ● Endocrinology
400 mg Ca2+/d
Absorption: 30–35%
PTH +
4
–
Calcitonin
+ –
Vit D
+ Abs Ca/PO
+
free
Ca Ca2+ Ca2+ + prot Plasma
PTH
i CaPO intestinal absorption
PO reabsorption
4
i production of 1,25 (OH)2 Vit D
Stimulates osteoclasts
i distal tubular reabsorption of Ca2+
Inhibition of bone resorption
Secreted by parafollicular cells of thyroid gland
Dietary endogenous Vit D3
OH-Vit D
Figure 2-10. Calcium Regulation
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
35
USMLE Step 2 l Internal Medicine
Treatment. For severe, life-threatening hypercalcemia, give vigorous fluid replacement with normal or half-normal saline, followed by a loop diuretic such as furosemide to promote cal- cium loss.
Use loop diuretic only after hydration in severe cases.
Use IV bisphosphonate such as zoledronate or pamidronate to inhibit osteoclasts and stimulate osteoblasts (maximum effect takes 2–3 days).
If fluid replacement and diuretics do not lower the calcium level quickly enough and you cannot wait the 2 days for the bisphosphonates to work, use calcitonin for a more rapid decrease in calcium level. Calcitonin inhibits osteoclasts.
Primary Hyperparathyroidism
Primary hyperparathyroidism represents 90% of mild hypercalcemias. It is most commonly due to adenoma of 1 gland (80%), but hyperplasia of all 4 glands can lead to primary hyper- parathyroidism (20%). Parathyroid cancer is a rare cause of this disease (<1%).
In MEN type I, hyperparathyroidism, pituitary tumors (3 “Ps”), and pancreatic tumors are seen.
In MEN type II, hyperparathyroidism, pheochromocytoma, and medullary carcinoma of the thyroid are seen.
Clinical Findings. 50% of patients with hyperparathyroidism are asymptomatic. Osteitis fibrosa cystica with hyperparathyroidism occurs because of increased rate of osteoclastic bone resorp- tion and results in bone pain, fractures, swelling, deformity, areas of demineralization, bone cysts, and brown tumors (punched-out lesions producing a salt-and-pepper-like appearance). Urinary tract manifestations of hypercalcemia include polyuria, polydipsia, stones, and nephrocalcinosis with renal failure (the polyuria and polydipsia are from NDI). Neurologic manifestations include CNS problems, mild personality disturbance, severe psychiatric disorders, mental obtundation or coma, neuromuscular weakness, easy fatigability, and atrophy of muscles. GI manifestations include anorexia, weight loss, constipation, nausea, vomiting, thirst, abdominal pain with pancreatitis, and peptic ulcer disease. Cardiovascular findings include hypertension and arrhyth- mias (short QT).
Diagnosis. Lab findings will include serum calcium >10.5 mg/dL, with elevated PTH. Urine calcium elevation is common, but because of the calcium-reabsorbing action of PTH, 35% of patients may have normal levels. Serum phosphate is usually low (<2.5 mg/dL). The differential diagnosis includes all other causes of hypercalcemia, especially hypercalcemia of malignancy. In every other cause of hypercalcemia, the PTH level will be low. In primary hyperparathy- roidism, PTH is always elevated.
Imaging studies such as CT, MRI, sonography, and nuclear scan are not used to diagnose hyperparathyroidism. A nuclear parathyroid scan (sestamibi) can be used to localize the adenoma. When combined with a neck sonogram, specificity rises significantly.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
36
Chapter 2 ● Endocrinology
Treatment. Medical treatment, used if surgery is contraindicated or if serum calcium ≤11.5 mg/ dL and patient is asymptomatic, includes bisphosphonates (pamidronate).
Reduce dietary calcium to 400 mg/d
Give oral hydration with 2–3 L of fluid
Give phosphate supplementation with phospho-soda
Consider estrogen for hyperparathyroidism in postmenopausal women
Surgical removal of the parathyroid glands is effective. Imaging studies may help localize the site of the affected gland prior to surgery.
Parathyroidectomy should be performed if there are symptoms of hypercalcemia, bone disease, renal disease, or if the patient is pregnant. Asymptomatic mild increases in calcium from hyperparathyroidism do not necessarily need to be treated.
In primary hyperparathyroidism, surgery is indicated if any of the following are present:
Calcium >11.5 mg/dL
Renal insufficiency
Age <50
Nephrolithiasis
Osteoporosis
Emergency treatment for severe hypercalcemia includes IV normal saline to restore volume and rarely furosemide after hydration. Everyone gets IV bisphosphonates such as pamidronate. Bisphosphonates are useful only temporarily for hyperparathyroidism and may take 2–3 days to reach maximum effect.
Hungry bones syndrome is hypocalcemia that occurs after surgical removal of a hyperactive parathyroid gland, due to increased osteoblast activity. It usually presents with rapidly decreas- ing calcium, phosphate, and magnesium 1–4 weeks post-parathyroidectomy.
Cinacalcet is a calcimimetic agent that has some effect in hyperparathyroidism by shutting off the parathyroids. This increases the sensitivity of calcium sensing (basolateral membrane potential) on the parathyroid. Cinacalcet is used as treatment of secondary hyperparathyroid- ism in hemodialysis patients. It is also indicated for the treatment of hypercalcemia in patients with parathyroid carcinoma and in moderate-to-severe primary hyperparathyroidism uname- nable to surgery.
Note
Calcitonin is an intermediary measure while waiting for IV bisphosphonate to act.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
37
USMLE Step 2 l Internal Medicine
Note
Primary hyperparathyroidism is due to a hyperfunction of the parathyroid glands themselves. Most commonly, there is oversecretion of PTH due to a parathyroid adenoma. The elevated PTH then causes elevated serum calcium and low serum phosphate.
Secondary hyperparathyroidism is due to physiologic (i.e., appropriate) secretion of PTH by
the parathyroid glands in response to hypocalcemia (resulting vitamin D deficiency, chronic kidney disease, etc.). Serum calcium level is low (that is what causes the elevated PTH) and serum phosphate is low (because of elevated PTH). In the case of chronic kidney failure and anuria, the phosphate—in this form of secondary hyperparathyroidism—is elevated (the kidney is unable to ‘trash’ phosphate).
Tertiary hyperparathyroidism is seen with long-term secondary hyperparathyroidism, which can lead to hyperplasia of the parathyroid glands and a loss of response to serum calcium levels. It is most often seen in patients with chronic renal failure, and is an autonomous activity of the parathyroid glands. Treatment is sometimes surgical removal.
Hypocalcemia is most commonly caused by hypoparathyroidism, renal failure, hyperphosphatemia, and hypomagnesemia. Drugs such as loop diuretics, phenytoin, alendronate, and foscarnet will also lower calcium levels. Renal failure causes hypocalcemia because of the loss of activated 1,25-dihydroxy-vitamin D. This leads to decreased calcium absorption from the gut. In addition, hyperphosphatemia will cause the precipitation of calcium in tissues. Low magnesium levels from malnutrition of alcoholism prevent the release of parathyroid hormone from the parathyroid glands. Alkalosis decreases free calcium levels by causing increased binding of calcium to albumin. Pseudo hypocalcemia occurs with low albumin levels. The free calcium level remains normal, while the total calcium level decreases.
To correct for albumin, add 0.8 to calcium level for every 1 gram below 4 of albumin. Massive blood transfusion gives hypocalcemia because of binding of the calcium to the citrate in the transfused units of blood.
Clinical Findings. Hypocalcemia results in increased neural hyperexcitability such as seizures, tetany, circumoral numbness, and tingling of the extremities. Arrhythmias may develop because of a prolonged QT. Cataracts develop for unclear reasons.
Treatment of hypocalcemia is IV or oral calcium replacement, and vitamin D replacement as necessary.
Hypoparathyroidism
The most common cause of hypoparathyroidism is surgical removal of the thyroid. Low PTH levels are also seen in hereditary hypoparathyroidism, acquired hypoparathyroidism (surgical removal), and hypomagnesemia.
Magnesium deficiency prevents release of PTH from the gland. Hypomagnesemia occurs from decreased GI absorption or alcoholism. High PTH levels are seen in chronic renal failure, and decreased levels of active vitamin D, which is caused by decreased dietary intake or defective metabolism (secondary to anticonvulsant therapy or vitamin D-dependent rickets, type I).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
38
Chapter 2 ● Endocrinology
Ineffective vitamin D can also lead to high PTH levels; this is seen in intestinal malabsorption and vitamin D-dependent rickets, type II. Low or ineffective vitamin D is also associated with low calcium levels.
Clinical Findings. Clinical findings depend on the level of calcium, duration, acid-base disorder, and age at onset of disease.
Neuromuscular irritability: tetany, laryngospasm, cramping, seizures, impaired memory function
Possible positive Chvostek sign (percussion of the facial nerve in front of ear, which elicits a contraction of facial muscles and upper lip)
Possible positive Trousseau sign (inflation of a blood pressure cuff on arm to a pressure higher than patient’s systolic pressure for 3 min elicits flexion of the metacar- pophalangeal joints and extension of interphalangeal joints)
Possible cardiovascular effects: QT prolongation, refractory CHF, and/or hypotension
Hypocalcemia frequently causes circumoral tingling as well as tingling of the hands and feet. Hyperventilation worsens symptoms of hypocalcemia because the alkalosis decreases free calcium levels.
Diagnosis is suggested when serum calcium is low; it is important to check albumin and make the correction in calcium level. A low calcium may be due to low albumin; for a 1.0 g/dL drop in albumin, total calcium will decrease by 0.8 mg/dL. It is better to measure ionized calcium.
Depending on the etiology, PTH can be low (hypoparathyroidism) or high. Low calcium with high phosphorous can be due to renal failure, massive tissue destruction, hypoparathyroidism, and pseudohypoparathyroidism. Low calcium with low phosphorous is due to absent or ineffective vitamin D.
Management. In the acute stage of hypocalcemia, give IV calcium gluconate. Maintenance therapy includes oral calcium 2–4 g/d, vitamin D, and if there is hyperphosphatemia, diet restriction and phosphate binders (CaCO3 or aluminum hydroxide).
Clinical Recall
Which of the following is a clear indication for surgery in a patient with primary hyperparathyroidism?
Calcium level 10.5 mg/dL
Creatinine level 1.0 mg/dL
EKG showing prolonged QT interval
Male gender, age 38
DEXA T-score +1.0
Answer: D
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
39
USMLE Step 2 l Internal Medicine
DISORDERS OF CARBOHYDRATE METABOLISM
Diabetes Mellitus
Diabetes mellitus (DM) is a disorder of carbohydrate metabolism, caused by relative or absolute deficiency of insulin, hyperglycemia, and end-organ complications (e.g., nephropathy, retinopathy, neuropathy, accelerated atherosclerosis). DM affects approximately 6% of the population in the United States, and approaches 20% of patients over age 65.
Classification
Type 1 IDDM (insulin-dependent or juvenile onset) accounts for 5–10% of diabetes worldwide, with males = females. The age of onset is usually age <30. Genetically, <10% of first-degree relatives are affected with a 50% occurrence in identical twins.
There is an increased prevalence of autoantibodies to islet cells, glutamic acid decar- boxylase (GAD), and other tissues with IDDM. Type 1 diabetes is associated with HLA-B8, HLA-B15, HLA-DR3, and HLA-DR4. Patients usually have a lean body build and are prone to ketosis owing to absent insulin production.
Type 2, or NIDDM (non-insulin-dependent or maturity onset), is the most common type of diabetes, accounting for 90% of cases, with males >females. Age of onset is usually age 40. Genetically >20% of first-degree relatives are affected with 90–100% occurrence in identical twins.
No autoantibodies are associated with NIDDM. The body build of these patients is usually obese with >80% being >15% above ideal body weight. NIDDM patients are ketosis-resistant, and insulin levels may be high, normal, or low. About 90% of diabetes is type 2.
For IDDM, by the time the condition appears, most of the beta cells in the pancreas have been destroyed. The destructive process is most likely autoimmune in nature.
For NIDDM, there are 2 clear physiologic defects: abnormal insulin secretion and resistance to insulin action in target tissues.
Clinical Findings. Manifestations of symptomatic DM vary from patient to patient. Most often symptoms are associated with hyperglycemia, and polyuria, polydipsia, and polyphagia can be seen. The first event may be an acute metabolic decompensation, resulting in coma (ketoacidosis for IDDM and hyperosmolar coma for NIDDM). Occasionally the initial expression of DM is a degenerative complication like neuropathy.
Diagnosis. Symptomatic patients will have polyuria, polydipsia, ketonuria, and weight loss. Plasma glucose >200 mg/dL in these patients is sufficient for diagnosis with no further testing needed. A random glucose >200 mg/dL is diagnostic.
In asymptomatic patients, an elevated plasma or urine glucose during routine screening does not establish diagnosis but indicates a need for further evaluation. Patients who have DM will have a fasting plasma glucose ≥126 mg/dL on 2 occasions. The oral glucose tolerance test is rarely required. DM is diagnosed when plasma glucose ≥200 mg/dL at 2 h and on at least one of the earlier samples. HbA1c >6.5% is diagnostic of diabetes.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
40
Chapter 2 ● Endocrinology
Glycosylated hemoglobin A1c (HbA1c) is produced by nonenzymatic condensation of glucose molecules with free amino groups on the globin component of hemoglobin. It is used both for diagnosis and to follow compliance of the treatment and glucose control in diabetic patients.
HbA1c is high in diabetics with chronic hyperglycemia during the preceding 8–12 weeks.
Management. The objectives of diabetic therapy are to control symptoms, prevent acute complications, and limit long-term complications. Several steps should be considered, such as patient education, weight loss, low-fat diet, physical activity, and pharmacologic therapy with oral hypoglycemic drugs or insulin.
Weight reduction of as little as 4–7% body fat has an enormous effect on peripheral insulin sensitivity and on reduction of postprandial hyperglycemia. Exercise lowers glucose levels. Exercising muscle needs no insulin for glucose to enter. Resting muscle, in comparison, needs insulin for glucose entry. As many as 25% of diabetic patients can be kept off of medication with diet and exercise alone.
The effects of diet, exercise, and weight loss can last for many years. When diet and exercise do not keep the HbA1c <7%, medications are introduced.
Oral hypoglycemics should be prescribed for all type 2 diabetics. Metformin is the drug of choice and along with lifestyle intervention should be used in all newly diagnosed patients. One major advantage of metformin is that it does not cause hypoglycemia. Another is that it does not cause weight gain. (Metformin is contraindicated in those with renal insufficiency.)
If a patient is initiated on metformin yet the diabetes does not become well-controlled, add a sulfonylurea.
If a patient is already on sulfonylurea but the diabetes is not well-controlled, add metformin.
If a patient is already taking both metformin and a sulfonylurea yet there is still poor glycemic control, then either switch to insulin or add a glitazone.
If metformin cannot be used, use a new glucagon-like peptide (GLP-1) agonist (exenatide or liraglutide). GLP-1 agonists are second-line agents that can be added to metformin or used individually if metformin cannot be used.
In all cases, metformin is clearly the “best initial therapy” for type 2 diabetes. After metformin, the choices are less clear.
Sulfonylureas (glyburide, glipizide, glimepiride): increase weight, cause hypoglycemia; sulfa drugs
Thiazolidinediones (rosiglitazone or pioglitazone): can worsen CHF
Thought to act by decreasing the resistance of tissues to insulin
Recent studies suggest pioglitazone may be linked to bladder cancer
Rosiglitazone only available through a special assessment program
Incretin mimetics (exenatide, liraglutide): must be given by injection
Augment the naturally occurring hormones that are secreted from the GI tract in response to food; when food enters the intestine, incretins are released
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
41
USMLE Step 2 l Internal Medicine
Increase the release of insulin from the pancreas
Also called gastric inhibitory peptide or glucose-dependent insulinotropic peptide (both abbreviated as GIP); GIP increases insulin release and slows gastric motility
The “incretin mimetic” drugs exenatide and liraglutide are direct analogues of GIP and GLP, except that their actions last much longer. The problem with these drugs is that they must be given by injection. They have an outstanding effect on slowing gastric motility and promoting weight loss, but because they are given by injection they are not used as one of the first 3 classes of medications to treat type 2 diabetes.
The other incretin is “glucagon-like peptide” or GLP. Though “glucagon-like,” GLP does not raise glucose levels or mimic the effect on glucagon in terms of breaking down glycogen or increasing gluconeogenesis. The term “glucagon-like peptide” is very confusing because the effect of GLP is strictly to LOWER glucose levels. GLP also raises insulin levels and slows gastric motility. GLP is normally released from the small bowel but in the native form lasts only for 2 minutes.
Dipeptidyl peptidase IV (DPP-IV) inhibitors (sitagliptin, saxagliptin, linagliptin): natural hormones which prevent the metabolism of the incretins GIP and GLP
Increase insulin release from the pancreas and slow stomach emptying
Only after therapy with multiple oral hypoglycemic fails should an insulin regimen be consid- ered. When starting insulin, divide 50% into long-acting and 50% into pre-meal short-acting. This regimen is usually given as glargine insulin 1x/day injection along with 2–3×/day ultra- short-acting insulin such as lispro or aspart before meals. Glargine causes fewer episodes of hypoglycemia compared with NPH. Levemir is a newer, long-acting insulin, lasting 16–18 hours.
Table 2-4. Oral Hypoglycemic Drugs
Brand Name | Doses/Day | ||
Micronase, Diabeta, Amaryl | 1–2 | ||
Glucophage | 2–3 | ||
1 | |||
Glucosidase inhibitors | Acarbose, miglitol | Precose | With every meal |
Meglitinides | Repaglinide, nateglinide | — | — |
DPP-IV inhibitors | Sitagliptin, saxagliptin, linagliptin | Januvia, Onglyza, Tradjenta | — |
Subcutaneous agents | |||
GLP-1 | Exenatide, liraglutide | Byetta, Victoza | 2/day, 1/day |
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
42
Chapter 2 ● Endocrinology
Table 2-5. Insulin Preparations
Type | Peak Action (Hours) | Duration of Action (Hours) |
Ultra-short-acting | ||
Insulin lispro Insulin aspart | 30–60 min 20–30 min | 4–6 3–5 |
Rapid | ||
Regular Semilente | 2–4 2–6 | 6–8 10–12 |
Intermediate | ||
NPH Lente | 6–12 | 12–18 |
Long-acting | ||
Glargine Levemir |
Clinical Recall
PO glyburide
PO chlorpropamide
PO arcarbose
IM insulin glargine
PO metformin
Answer: E
Complications of diabetes mellitus
Acute Complications. Diabetic ketoacidosis (DKA) is a result of severe insulin insufficiency. It occurs in type 1 diabetics and may be the presenting manifestation. Precipitating factors of DKA include insufficient or interrupted insulin therapy, infection, emotional stress, and excessive alcohol ingestion.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
43
USMLE Step 2 l Internal Medicine
Insulin Deficiency
glucose uptake
proteolysis
amino acids
Hyperglycemia
Gluconeogenesis
+
glycogenolysis
lipolysis
free fatty acids
nitrogen loss
glycerol
ketogenesis
ketonuria
ketonemia
Figure 2-11. Pathophysiology of DKA
The main problems in DKA stem from acidosis with increased anion gap and dehydration. Clinical findings include anorexia, nausea or vomiting, abdominal pain, rapid breathing (Kussmaul respiration), “fruity” breath odor of acetone, signs of dehydration (dry skin and mucous membranes and poor skin turgor), and altered consciousness to coma. Acidosis can result in fatal rhythm disturbance.
The diagnosis of DKA can be made by finding elevated blood glucose, increased serum levels of acetoacetate, acetone, and hydroxybutyrate, metabolic acidosis (low serum bicarbonate and low blood pH), and increased anion gap (sodium – [bicarbonate + chloride]). DKA is man- aged with insulin, fluids, and electrolyte replacement. Normal saline should be given in high volume with insulin replacement. Bolus with 5–10 units of regular insulin. Acutely, DKA is associated with hyperkalemia. The total body level of potassium is depleted because of the urinary loss of potassium. As soon as the potassium level falls to ≤5 mEq/L, potassium replace- ment should be given.
Clinical points in the management of DKA
Begin management with IV insulin, then switch to subcutaneous insulin when the anion gap normalizes and serum bicarbonate levels are normal.
Do not stop the IV insulin before starting subcutaneous insulin; instead, overlap them both for 6−8 hours.
Add 5% dextrose to the normal saline as blood glucose reaches 200−250 mg/dL, and continue IV insulin until the anion gap normalizes.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
44
Chapter 2 ● Endocrinology
Hyperosmolar nonketotic coma (HONK) is a syndrome that occurs predominantly in patients with type 2 diabetes and is characterized by severe hyperglycemia in the absence of significant ketosis. Precipitating factors include noncompliance with treatment plus the inability to drink sufficient water to keep up with urinary losses. This is common in elderly diabetics living in nursing homes. Infections, strokes, steroids, immunosuppressant agents, and diuretics are other precipitating factors. HONK can occur after a therapeutic procedure such as peritoneal/hemodi- alysis, tube feeding of high-protein formulas, or high-carbohydrate infusion. The pathophysiol- ogy involved is profound dehydration resulting from a sustained hyperglycemic diuresis. Clinical findings are weakness, polyuria, polydipsia, lethargy, confusion, convulsions, and coma.
The diagnosis of HONK is suggested by elevated blood glucose (typically ≥700 mg/dL) and extremely high serum osmolality.
Serum osmolality in mOsm/L = 2[sodium] + [glucose/18] + [BUN/2.8]
A high BUN (prerenal azotemia) and mild metabolic acidosis (bicarbonate ~20 mEq/L) is also seen without ketosis.
Management of HONK involves high-volume fluid and electrolyte replacement, and insulin.
Chronic Complications. Chronic complications of diabetes involve the macro- and microvas- culature, and are a major result of disease progression. These complications reduce patients’ quality of life, incur heavy burdens to the health care system, and increase diabetic mortality. Microvascular disease of diabetes includes diabetic nephropathy, neuropathy, and retinopathy. Macrovascular disease contains coronary artery disease, peripheral arterial disease, and stroke. The effect of glycemic control is much more evident on the morbidity and mortality associated with microvascular complications.
Cardiovascular Complications. The number 1 cause of death in patients with diabetes is cardiovascular disease. About 75% of all deaths in diabetes are from myocardial infarction, congestive failure, or stroke. The central pathological mechanism in macrovascular disease is atherosclerosis, which leads to narrowing of arterial walls throughout the body. Atherosclero- sis is thought to result from chronic inflammation and injury to the arterial wall in the peripheral or coronary vascular system.
Lipid testing should be performed in patients with diabetes at least annually. Diabetes is con- sidered the equivalent of coronary disease in terms of management of hyperlipidemia. Lipid goals for adults with diabetes are as follows:
LDL <100 mg/dL (or <70 mg/dL in cases of overt CVD)
HDL >50 mg/dL
Fasting triglycerides <150 mg/dL
If LDL >100 mg/dL, patient should implement lifestyle modification (diet, exercise) along with drug therapy (statin). Combination therapy of statin plus another drug such as a fibrate or niacin may be necessary to achieve ideal lipid control, but monitor patients closely for possible adverse reaction to therapy.
Coronary artery bypass should be performed in a diabetic patient even if there is only 2-vessel coronary disease.
Diabetic nephropathy. Nephropathy affects 30–40% of type 1 diabetics and 20–30% of type 2 diabetics. Hyperproliferation, proteinuria, and end-stage renal disease can develop. The pathology can be diffuse, which is more common, and lead to widening of glomerular basement membrane and mesangial thickening. Nodular pathology can occur and results in hyalinization of afferent
Note
The most common pattern of dyslipidemia in patients with type 2 diabetes is elevated triglyceride and decreased HDL cholesterol.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
45
USMLE Step 2 l Internal Medicine
glomerular arterioles (Kimmelstiel-Wilson syndrome). Management of nephropathy involves strict control of diabetes, ACE-inhibitors, and dialysis or renal transplantation.
All diabetics should be screened for proteinuria annually. Proteinuria is detectable on a standard dipstick when the level >300 mg per 24 hours. Microalbuminuria is defined as a level 30–300 mg. All those with proteinuria should receive therapy with an ACE inhibitor or angiotensin receptor blocker. Diabetes is the most common cause of end-stage renal disease in the United States.
Diabetic retinopathy. The retina is affected, and diabetes is the leading cause of blindness in middle-aged patients. Simple/background, or proliferative (microaneurysms, hemorrhages, exudates, retinal edema) damage can occur.
For type 2 diabetic patients, screen at diagnosis, then annually.
For type 1 diabetes, the first screening should take place 5 years after diagnosis, then annually.
Proliferative retinopathy is defined as the presence of vitreous hemorrhages or neovasculariza- tion; treatment is with laser photocoagulation. Nonproliferative or background retinopathy can only be prevented with tight control of glucose levels.
Diabetic neuropathy. Neuropathy is another complication of diabetes, and it has various types.
Peripheral neuropathy (most common) is symmetrical, with symptoms of numbness, paresthesia, and pain being prevalent. Physical exam reveals absent reflexes and loss of vibratory sense. Podiatric exam (microfilament testing) should occur annually to look for early signs of neuropathy since it leads to increased injury from trauma. Diabetes is responsible for 50% of all nontraumatic amputations in the United States.
Mononeuropathy affects a single nerve or nerve trunk (mononeuritis multiplex) and is vascular in origin; patients will have sudden foot drop, wrist drop, or paralysis of CN III, IV, or VI.
Autonomic neuropathy can be devastating; patients will have orthostatic hypotension and syncope as main manifestations. Gastrointestinally, patients may have difficulty swallowing, delayed gastric emptying (gastroparesis), constipation, or diarrhea. The diagnostic test of choice for gastroparesis is the gastric emptying scintigraphy study. Bladder dysfunction or paralysis can lead to urinary retention. Impotence and retrograde ejaculation can occur; the prevalence of erectile dysfunction is as high as 50% in patients with 10 years of diabetes.
Wikimedia, Jonathan Moore
Figure 2-12. Diabetic Foot Ulcer
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
46
Chapter 2 ● Endocrinology
As with other microvascular complications, prevention of neuropathy in diabetes is by tight glycemic control. Management once it occurs depends on the type. For peripheral neuropathy, analgesics, gabapentin, pregabalin, amitriptyline, and carbamazepine are used (gabapentin and pregabalin are the best). For gastroparesis, metoclopramide or erythromycin can be used.
Erectile dysfunction is treated with sildenafil and similar drugs.
Additional Concepts. The “honeymoon” period (in IDDM patients) is an initial episode of ketoacidosis followed by a symptom-free interval during which no treatment is required. Presum- ably stress-induced epinephrine release blocks insulin secretion, causing the syndrome. In normal individuals insulin reserve is such that hormone release is adequate even in the face of stress.
The Somogyi effect is rebound hyperglycemia in the morning because of counterregulatory hormone release after an episode of hypoglycemia in the middle of the night.
The Dawn phenomenon is an early morning rise in plasma glucose secondary to a rise in counter-regulatory hormones cortisol, epinephrine, and GH requiring increased amounts of insulin to maintain euglycemia.
Hypoglycemia
Glucose is the primary energy source of the brain. Symptoms of hypoglycemia are divided into 2 groups and can occur because of excessive secretion of epinephrine, leading to sweat- ing, tremor, tachycardia, anxiety, and hunger. Hypoglycemia can also occur because of dysfunction of the CNS, leading to dizziness, headache, clouding vision, blunted mental activity, loss of fine motor skills, confusion, abnormal behavior, convulsions, and loss of consciousness. There is no uniform correlation between a given level of blood sugar and symptoms. Major symptoms in normal persons may not be seen until blood sugar is
20 mg/dL.
Classification. Postprandial hypoglycemia (reactive) can be secondary to alimentary hyperin- sulinism (after gastrectomy, gastrojejunostomy, pyloroplasty, or vagotomy), idiopathic, and galactosemia.
Fasting hypoglycemia can result from conditions in which there is an underproduction of glucose, such as hormone deficiencies (panhypopituitarism, adrenal insufficiency), enzyme defects, substrate deficiency (severe malnutrition, late pregnancy), acquired liver disease, or drugs (alcohol, propanolol, salicylates). Fasting hypoglycemia can also occur in conditions related to overutilization of glucose such as hyperinsulinism. Hyperinsulinism can occur secondary to insulinoma, exogenous insulin, sulfonylureas, drugs (quinine), endotoxic shock, and immune disease with insulin receptor antibodies. Overutilization of glucose can also occur in states in which there are appropriate insulin levels, such as extrapancreatic tumors and rare enzyme deficiencies.
Insulinoma (pancreatic B-cell tumor) can cause hypoglycemia. Ninety percent of these tumors are single and benign. Clinical findings include symptoms of subacute or chronic hypoglycemia such as blurred vision, headache, feelings of detachment, slurred speech, and weakness.
Symptoms occur in the early morning or late afternoon or after fasting or exercise.
Diagnosis. This is made by finding a serum insulin level ≥8 mg/mL in the presence of blood glucose <40 mg/dL (i.e., inappropriately high serum insulin level when glucose is low), noted either spontaneously or during a prolonged fast (72 hours). CT scan, U/S, and arteriography may also be useful in detecting the tumor(s). Management of insulinoma is by surgery, diet, and medical therapy.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
47
USMLE Step 2 l Internal Medicine
Factitious hyperinsulinism is caused by self-administration of insulin or ingestion of Equal or oral sulfonylureas. It is common and exceeds the incidence of insulinomas. Most often, these patients are associated with the health professions or have access to these drugs by a diabetic member of the family. A triad of hypoglycemia, high immunoreactivity, insulin, and sup- pressed plasma C-peptide is pathognomonic of exogenous insulin administration.
Ethanol-induced hypoglycemia can also occur with prolonged starvation, when glycogen reserves become depleted in 18–24 hours and hepatic glucose output depends completely on gluconeogenesis. Ethanol at a concentration of 45 mg/dL can induce hypoglycemia by block- ing gluconeogenesis.
Table 2-6. Differential Diagnosis of Insulinoma and Factitious Hyperinsulinism
Test | Insulinoma | Exogenous Insulin | Sulfonylureas |
Plasma insulin | High (usually <200 | Very high (usually | High |
Normal or low | Normal | ||
Normal or low | Increased | ||
Absent | |||
Present |
Exenatide
Sitagliptin
Answer: C
DISEASES OF THE ADRENAL GLAND
The adrenal gland is divided into 2 areas: the cortex and medulla. The cortex is divided into 3 areas, the outer zone (glomerulosa), which is the site of aldosterone synthesis; the central zone (fasciculata), which is the site of cortisol synthesis; and the inner zone (reticularis), which is the site of androgen biosynthesis. The disorders of hyperfunction of the gland are associated with the following specific hormones: increased cortisol is seen in Cushing syn- drome; increased aldosterone in hyperaldosteronism; and increased adrenal androgens with virilization in women.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
48
Chapter 2 ● Endocrinology
Region
Hormones Controlled by
Capsule
Zona
Glomerulosa
Aldosterone
Angiotensin II, [K+]
Zona
Fasciculata
Cortisol
and
ACTH
Zona
Reticularis
Androgens
(LH has no effect on the production
of adrenal androgens)
Figure 2-13. Adrenal Cortex Regions
Cushing syndrome
Cushing syndrome is a group of clinical abnormalities caused by prolonged exposure to increased amounts of cortisol or related corticosteroids. The most common causes are exogenous, iatrogenic, and those secondary to prolonged use of glucocorticoids.
The etiology of Cushing syndrome includes adrenal hyperplasia. This can be secondary to pituitary ACTH production, which occurs in pituitary-hypothalamic dysfunction, and pituitary ACTH-producing adenomas (microadenoma, e.g., Cushing disease). ACTH- producing pituitary adenomas cause about 60–80% of Cushing cases. Adrenal hyperplasia can also be secondary to ACTH or corticotropin-releasing hormone (CRH), produced by nonen- docrine tumors (bronchogenic carcinoma, carcinoma of the thymus, pancreatic carcinoma, and bronchial adenoma). Adrenal neoplasia, such as adenoma or carcinoma, and adrenal nodular hyperplasia account for about 30% of Cushing cases. Excessive cortisol production by an autonomous adrenal tumor results in a low ACTH level. About 15% of Cushing cases are from ACTH from a source that cannot be located.
Clinical Findings. The clinical findings of Cushing syndrome include deposition of adipose tissue in characteristic sites such as upper fat, moon facies; interscapular buffalo hump; and mesenteric bed, truncal obesity. Other clinical findings include hypertension, muscle weakness, and fatigability related to mobilization of peripheral supportive tissue; osteoporosis caused by increased bone catabolism; cutaneous striae; and easy bruisability. Women may have acne, hirsutism, and oligomenorrhea or amenorrhea resulting from the increased adrenal androgen secretion. Emotional changes range from irritability or emotional lability to severe depression or confusion; even psychosis can occur as well. Glucose intolerance is common in Cushing disease, with 20% of patients having diabetes.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
49
USMLE Step 2 l Internal Medicine
Cushing and glucocorticoid use are also associated with hypokalemia and leukocytosis. Hypokalemia occurs because of the mineralocorticoid effect of the steroids.
Clinically significant hypokalemia is uncommon.
Other manifestations are delayed wound healing, renal calculi from increased calcium levels, and glaucoma. Polyuria is from hyperglycemia. There is increased susceptibility to infections because neutrophils exhibit diminished function because of high glucocorticoid levels.
Diagnosis. The diagnostic tests used to establish the syndrome of cortisol excess are the 1-mg overnight dexamethasone suppression test and the 24-hour urine-free cortisol. The tests used to establish a precise etiology of the cortisol excess are the ACTH level, high-dose dexametha- sone suppression test, CT and MRI scanning, and occasionally sampling of the petrosal venous sinus, which drains out of the pituitary.
The 1-mg overnight dexamethasone suppression test is used to rule out the diagnosis of Cushing syndrome or glucocorticoid excess. If you give a milligram of dexamethasone at 11 p.m., the cortisol level at 8 a.m. should come to normal if there is the normal ability to suppress ACTH production over several hours. The problem with this test is that there can be falsely abnormal or positive tests. Any drug that increases the metabolic breakdown of dexamethasone will prevent its ability to suppress cortisol levels. Examples of drugs increasing the metabolism of dexametha- sone are phenytoin, carbamazepine, and rifampin. Stress increases glucocorticoid levels. The
An abnormality on the 1-mg overnight test should be confirmed with a 24-hour urine-free cortisol. The 24-hour urine-free cortisol is more accurate and is the gold standard for confirm- ing or excluding Cushing’s syndrome.
A third screening test for Cushing is the midnight salivary cortisol. In normal patients, cortisol is at its lowest at midnight. In Cushing patients, cortisol is abnormally elevated at midnight.
The precise etiology of the Cushing syndrome is established by using ACTH levels, sometimes in combination with high-dose dexamethasone suppression testing. ACTH levels are elevated with either a pituitary source of ACTH such as an adenoma or with an ectopic source. High- dose dexamethasone suppression testing can distinguish the difference. The output of a pituitary adenoma will suppress with high-dose dexamethasone. The output of an ectopic source will not suppress with high-dose dexamethasone.
If the ACTH level is low, then the etiology is most likely from an adrenal tumor such as an adeno- ma, cancer, or from adrenal hyperplasia. When the adrenal gland is the source of increased cortisol production, there is feedback inhibition on the pituitary and the ACTH level is suppressed.
When there is a low ACTH level, the precise etiology is confirmed with a CT scan of the adrenals.
When there is a high ACTH level, the precise etiology is confirmed with an MRI of the pituitary looking for an adenoma or a CT scan of the chest looking for an ectopic focus.
If neither of these shows a lesion or the MRI of the brain is equivocal, then inferior petrosal sinus sampling should be done to see if there is increased ACTH coming out of the brain.
Single random cortisol levels are not reliable.
High plasma ACTH levels = pituitary or ectopic source
Low plasma ACTH levels = adrenal tumors or hyperplasia
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
50
Chapter 2 ● Endocrinology
Management. Depends on the etiology, and can be surgical or medical. Unresectable adrenal tumors are treated with ketoconazole or metyrapone.
Clinical suspicion
Osteoporosis Central adiposity Diabetes mellitus
Hirsutism amenorrhea
Overnight dexamethasone suppression test
Normal
No Cushing
Abnormal
(can be seen in obese, alcoholic or depressed individuals [false + ])
Dexamethasone suppression test (high dose)
Suppression to
<50% control
ACTH level | ||
ACTH-producing tumor
Adrenal neoplasia
Adrenal lesions: hyperplasia, adenoma, neoplasia
MRI pituitary
Pituitary adenoma (Cushing disease)
Low High
Adrenal hyperplasia due
to ACTH-producing tumor (lung)
CT chest
CT/MRI adrenals
Figure 2-14. Evaluating a Patient with Presumed Cushing Syndrome
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
51
USMLE Step 2 l Internal Medicine
Hyperaldosteronism
Hyperaldosteronism is a syndrome associated with hypersecretion of the major adrenal miner- alocorticoid, aldosterone. The normal function of aldosterone is to reabsorb sodium and excrete potassium and acid (H+). Hyperaldosteronism can be divided into the following:
Primary aldosteronism, in which the stimulus for the excessive aldosterone produc- tion is within the adrenal gland
Secondary aldosteronism, in which the stimulus is extraadrenal
The most common cause of primary hyperaldosteronism is a unilateral adrenal adenoma (70%). Bilateral hyperplasia accounts for 25–30%. Excessive black licorice ingestion can mimic this effect. Licorice has aldosterone-like qualities.
Secondary Aldosteronism
Initiating event
i Aldosterone production
Figure 2-15. Mechanism of Hyperaldosteronism
Clinical. Primary hyperaldosteronism is characterized by hypertension and low potassium levels. Most of the other symptoms, such as muscle weakness, polyuria, and polydipsia, are from the hypokalemia. Metabolic alkalosis occurs because aldosterone increases hydrogen ion (H+) excretion. Aldosterone causes alkalosis. Edema is uncommon with primary hyperaldosteronism because of sodium release into the urine.
Table 2-7. Clinical and Laboratory Findings in Primary and Secondary Aldosteronism
Primary Aldosteronism | Secondary Aldosteronism | |
Diastolic hypertension | + | – |
Muscle weakness | + | +/– |
Polyuria, polydipsia | + | +/– |
Edema | – | +/– |
Hypokalemia | + | + |
Hypernatremia | + | – |
Metabolic alkalosis | + | + |
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
52
Chapter 2 ● Endocrinology
Diagnosis. The preliminary screen for hyperaldosteronism is a plasma aldosterone concentra- tion (PAC) and plasma renin activity (PRA). A positive screen is a PAC/PRA ratio >20:1 and a PAC >15. To confirm hyperaldosteronism, an NaCl challenge is required. This can be via normal saline, NaCl tabs, or fludrocortisone. After an NaCl challenge, PAC should be sup- pressed as in a normal individual. If PAC is still elevated, this confirms the diagnosis.
Management. Adrenal adenomas are removed surgically. Bilateral hyperplasia is treated with spironolactone, which blocks aldosterone.
Bartter Syndrome. The exception of secondary hyperaldosteronism without edema or hypertension is Bartter syndrome. Bartter syndrome is caused by a defect in the loop of Henle in which it loses NaCl. This is due to a defect in the Na-K-2Cl cotransporter. This is like having a furosemide-secreting tumor.
In Bartter syndrome there is juxtaglomerular hyperplasia, normal to low blood pressure, no edema, severe hypokalemic alkalosis, defect in renal conservation of sodium or chloride, and renal loss of sodium, which stimulates renin secretion and aldosterone production.
Syndromes of adrenal androgen excess
Syndromes of adrenal androgen excess result from excess production of dehydroepiandros- terone (DHEA) and androstenedione, which are converted to testosterone in extraglandular tissues. The elevated testosterone accounts for most androgenic effects.
Clinical Signs and Symptoms. Hirsutism, oligomenorrhea, acne, and virilization. Etiology includes congenital adrenal hyperplasia, adrenal adenomas (rare), and adrenal carcinomas.
Congenital adrenal hyperplasia
Congenital adrenal hyperplasia (CAH) is the most common adrenal disorder of infancy and childhood. It is associated with increased adrenal androgen production because of enzymatic defects. CAH arises from autosomal recessive mutations, which produce deficiencies of enzymes necessary for the synthesis of cortisol.
Common Enzymatic Defects Associated with CAH. Enzymatic defects include C-21 hydroxylase deficiency in 95% of all cases. C-21 hydroxylase deficiency is associated with reduction in aldosterone secretion in one-third of patients. Adrenal virilization occurs with or without an associated salt-losing tendency, owing to aldosterone deficiency, which leads to hyponatremia, hyperkalemia, dehydration, and hypotension.
Patients are female at birth with ambiguous external genitalia (female pseudohermaphroditism), enlarged clitoris, and partial or complete fusion of the labia. Postnatally CAH is associated with virilization. Patients may be male at birth with macrogenitosomia; postnatally this is associated with precocious puberty.
hydroxylase deficiency can also occur. The mineralocorticoid manifestations in C-11 deficiency can be ‘biphasic.’ In early infancy, despite having excessive mineralocorticoid hormones, patients sometimes present with relative ‘salt wasting’ (aldosterone deficiency). This is because some infants have inefficient salt conservation as well as immature aldosterone production.
During this phase, infants can present with hypotension and hyperkalemia (very similar to 21 hydroxylase deficiency). Later in life (childhood and adulthood), there is better ability to hold onto salt, so the patient develops the typical C-11 deficiency syndrome: hypertension and hypokalemia.
Note
The ‘biphasic’ presentation is rare. When you think about 11 deficiency, think mineralocorticoid excess (hypertension and
hypokalemia) with low cortisol production (remember you need C-11 for the final step in converting to cortisol).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
53
USMLE Step 2 l Internal Medicine
hydroxylase deficiency can occur as well, and is characterized by hypogonadism, hypoka- lemia, and hypertension resulting from increased production of 11-deoxycorticosterone.
Diagnosis. CAH should be considered in all infants exhibiting failure to thrive, especially those with episodes of acute adrenal insufficiency, salt wasting, or hypertension. The most useful measurements are of serum testosterone, androstenedione, dehydroepiandrosterone, 17-hydroxyprogesterone, urinary 17-ketosteroid, and pregnanetriol.
Management. Treatment is glucocorticoid (hydrocortisone) replacement.
Clinical Recall
An elderly, obese, diabetic patient comes to the clinic with LDL levels of 150 mg/dL. Which medication should be given at this time?
Answer: B
Adrenal insufficiency can be divided into primary adrenocorticoid insufficiency (Addison disease) and secondary failure in the elaboration of ACTH.
Primary adrenocortical insufficiency is a slow, usually progressive disease due to adrenocorti- coid hypofunction. The etiology can be secondary to anatomic destruction of the gland (chronic and acute). Idiopathic atrophy is the most common cause of anatomic destruction, and autoimmune mechanisms are probably responsible. Autoimmune destruction accounts for 80% of cases. Anatomic destruction can also be secondary to surgical removal, infection (TB, fungal, cytomegalovirus), hemorrhagic, trauma, and metastatic invasion. Metabolic failure in hormone production can also lead to Addison disease and can be secondary to CAH, enzyme inhibitors, and cytotoxic agents (mitotane).
Clinical Findings. The clinical findings in Addison disease include weakness, paresthesias, cramping, intolerance to stress, and personality changes such as irritability and restlessness. Chronic disease is characterized by a small heart, weight loss, and sparse axillary hair. Hyper- pigmentation of the skin can occur and appears as diffuse brown, tan, or bronze darkening of both exposed and unexposed body parts. Arterial hypotension is seen and is often orthostatic owing to lack of effect of cortisol on vascular tone. Abnormalities of GI function are found, and symptoms vary from mild anorexia with weight loss to nausea, vomiting, diarrhea, and abdominal pain. Acute Addisonian crisis is characterized by fever and hypotension. A low sodium with a high potassium level and mild acidosis are also present.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
54
Chapter 2 ● Endocrinology
Diagnosis. The diagnosis of Addison disease is made through rapid ACTH administration and measurement of cortisol. Laboratory findings include white blood cell count with moderate neutropenia, lymphocytosis, and eosinophilia; elevated serum potassium and urea nitrogen; low sodium; low blood glucose; and morning low plasma cortisol.
The definitive diagnosis is the cosyntropin or ACTH stimulation test. A cortisol level is obtained before and after administering ACTH. A normal person should show a brisk rise in cortisol level after ACTH administration.
Differences between primary and secondary adrenal insufficiency:
Hyperpigmentation (occurs only with primary insufficiency)
Electrolyte abnormalities
Hypotension
Plasma cortisol 30–60 minutes after 250 g cosyntropin IM or IV
Primary
High ACTH Subnormal aldosterone increment
Primary adrenal insufficiency
Low ACTH
Normal aldosterone increment
Secondary adrenal insufficiency
Figure 2-16. Diagnosis of Adrenal Insufficiency
Management. The management of Addison disease involves glucocorticoid, mineralocorticoid, and sodium chloride replacement, in addition to patient education.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
55
USMLE Step 2 l Internal Medicine
Adrenal Crisis. In an adrenal crisis, fever, vomiting, abdominal pain, altered mental status, and vascular collapse may occur. Get a cortisol level, then rapidly administer fluids and hydrocortisone. This may occur in:
Previously undiagnosed patient with adrenal insufficiency who has undergone surgery, serious infection, and/or major stress
Bilateral adrenal infarction or hemorrhage
Patient who is abruptly withdrawn from chronic glucocorticoid therapy
Pheochromocytoma
Pheochromocytoma is a rare, usually benign, tumor that arises from the chromaffin cells of the sympathetic nervous system. The rule of 10% applies in pheochromocytoma with 10% being extraadrenal, 10% malignant, 10% in children, and 10% bilateral or multiple (>right side). Also, 10% are not associated with hypertension.
Epidemiology. Pheochromocytoma occurs in approximately 0.1% of the hypertensive population. Familial pheochromocytoma occurs in 5% of cases, and is transmitted as an autosomal dominant trait alone or in combination with MEN type IIa or IIb, von Recklinghau- sen neurofibromatosis, or von Hippel-Lindau retinal cerebellar hemangioblastomatosis.
Pathology. In adults, 80% of pheochromocytomas occur as a unilateral solitary lesion with 10% being bilateral and 10% extraadrenal. In children, 25% of the tumors are bilateral and 25% are extraadrenal. Solitary lesions favor the right side. Extraadrenal pheochromocytomas are mostly located within the abdomen and near the celiac, superior mesenteric, and inferior mesenteric ganglia.
Catecholamine Secretion. Secretion of dopamine occurs more in familial syndromes and is not associated with hypertension. Epinephrine secretion causes tachycardia, sweating, flush- ing, and hypertension. Norepinephrine is secreted by all extraadrenal tumors.
Clinical Findings. Clinical findings of pheochromocytoma include paroxysms or crisis. This accounts for the typical manifestations occurring in >50% of patients. The attack has a sudden onset, lasting from a few minutes to several hours or longer. Headache, profuse sweating, palpitations, and apprehension are common in this setting. Pain in the chest or abdomen may be associated with nausea and vomiting. Blood pressure is elevated with tachycardia in crisis. Forty percent of patients have blood pressure elevation only during the attack, and 60% have stable hypertension. Anxiety, tremor, and weight loss are also found.
>33% of pheochromocytomas cause death prior to diagnosis; death is often due to cardiac arrhythmia and stroke.
Other clinical features include orthostatic hypotension and glucose intolerance. The hypergly- cemia is only found in about 33% of patients and is mild.
Diagnosis. Diagnosis is established by demonstrating increased amounts of catecholamines or catecholamine metabolites in a 24-hour urine collection. Urinary-free catecholamines, urinary metanephrines, vanillylmandelic acid, and plasma catecholamines are tests of choice. Meta- nephrines are catecholamine metabolites. A 24-hour urinary VMA, metanephrines, and free catecholamines are the best initial tests. Recently, plasma metanephrine levels have been used in conjunction with urinary tests. Overall, metanephrines are the most sensitive and specific individual test. Smoking can increase plasma-free metanephrines. The patient must not smoke at least 4 hours before the test.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
56
Chapter 2 ● Endocrinology
Clonidine should suppress epinephrine levels. Failure of epinephrine levels to fall after clonidine administration is highly suggestive of pheochromocytoma. A clonidine-suppression test is used when the screening tests are equivocal.
When the catecholamine or metanephrine levels are abnormal, the tumor is confirmed with CT or MRI scan. If the biochemical tests (catecholamines, metanephrines) are positive and the CT scan does not show the location of the pheochromocytoma, then do an MIBG (metaiodo- benzylguanidine) scan.
The differential diagnosis of pheochromocytoma includes essential hypertension, anxiety attacks, factitious crisis, intracranial lesions, and autonomic epilepsy.
Management. Alpha-adrenergic blockade, phentolamine and/or phenoxybenzamine, is required to control BP and prevent a hypertensive crisis, since high circulating catecholamine levels stimulate alpha receptors on blood vessels and cause vasoconstriction.
Beta blockers are used if significant tachycardia occurs after alpha blockade; beta blockers are not administered until adequate alpha blockade has been established, since unopposed alpha-adrenergic receptor stimulation can precipitate a hypertensive crisis.
Noncardioselective beta blockers (propranolol, nadolol) are the usual choice, though cardioselective agents (atenolol, metoprolol) may be used.
Labetalol has been associated with paradoxic episodes of hypertension thought to be secondary to incomplete alpha blockade.
Curative surgical removal of the pheochromocytoma is performed only after BP has been stabilized; during surgery, IV phentolamine—a rapid-acting alpha-adrenergic antagonist—is used for controlling BP.
DISEASES OF THE TESTES, HYPOGONADISM
In hypogonadism there is decreased function of the testes or ovaries, resulting in the absence or impairment of secondary sexual characteristics and infertility.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
57
USMLE Step 2 l Internal Medicine
Note
Males affected by Klinefelter syndrome have a 20 × increased risk of breast
cancer .
Primary hypogonadism (hypergonadotropic: increased LH, FSH) can result from Klinefelter syndrome (small testes, eunuchoid, 47XXY), anorchia, surgical or acciden- tal castration or radiotherapy, infections (mumps, TB, leprosy), or chemotherapeutic agents.
Secondary hypogonadism (hypogonadotropic: low LH, FSH) can result from hypopituitarism secondary to idiopathic causes or tumors, hypothalamic lesions, and Kallmann syndrome (hypogonadic hypogonadism, associated with decreased sense of smell).
Clinical Findings.
Prepubertal hypogonadism, usually caused by a specific gonadotropic deficiency of the pituitary
Underdeveloped external genitalia, high-pitched voice, beard that does not grow, lack of libido and potency
Low to normal urinary 17-ketosteroid and below-normal serum testosterone
Serum FSH and LH: low in hypothalamic or pituitary origin but elevated in primary testicular failure
Klinefelter syndrome is the most common primary developmental abnormality causing hypogonadism (testicular damage), affecting 1 of every 400–500 males. It is caused by one or more supernumerary X chromosomes.
Sterility and lack of libido
Small and thin testes
Possible intellectual disability
Low-normal or normal urinary 17-ketosteroids; low to normal serum testosterone; elevated LH and FSH; and elevated serum estradiol
Treatment is testosterone replacement.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
58
Chapter 2 ● Endocrinology
Clinical Recall
Which of the following tests are most specific in the diagnosis of pheochromocytoma?
Urinary-free catecholamines with plasma catecholamine
24 hour urinary VMA and free catecholamines
Urinary VMA with plasma catecholamine
Plasma catecholamines and VMA with urinary VMA and catecholamine levels
Plasma metanephrine with 24 hour urinary metanephrine and VMA levels
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
59
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
RhCehuamptaetroTloitglye #3
Learning Objectives
List the steps for evaluating a patient with arthritis
Differentiate between autoimmune arthritis, seronegative arthritis, osteoarthritis, crystal-induced arthritis, and septic arthritis
Differentiate and describe the treatment approaches to rheumatoid arthritis, systemic lupus erythematosus, drug-induced lupus, scleroderma, Sjögren syndrome
Differentiate and describe treatment approaches to seronegative arthropathies, including ankylosing spondylitis, reactive arthritis, psoriatic arthritis, and entero- pathic arthritis
Answer questions about the management of osteoarthritis, crystal-induced arthropa- thies, and septic arthritis
Describe the diagnosis and management of vasculitis syndromes and inflammatory myopathies
EVALUATING A PATIENT WITH ARTHRITIS
When a patient presents with joint swelling, a differential diagnosis is generated based on the answers to the following questions:
What is the distribution of joint involvement and how many joints are involved?
Polyarticular symmetric involvement is characteristically seen with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), parvovirus B19, and hepatitis B.
Monoarticular arthritis is consistent with osteoarthritis (OA), crystal-induced arthritis (gout, pseudogout), septic arthritis (gonococcus), trauma, and hemarthrosis.
Migratory arthropathy (inflammation and pain migrate from joint to joint while the previous involved joints improve) is caused by rheumatic fever, disseminated gonococcal infection, and Lyme disease.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
61
USMLE Step 2 l Internal Medicine
Oligoarticular asymmetric arthritis is common with the spondyloarthropathies (ankylosing spondylitis) and OA involving the small joint of the upper extremities. It is rarely in the presentation of polyarticular gout.
Are the symptoms acute or chronic?
OA is a chronic disease; patients have symptoms for months to years. With septic arthritis or crystal-induced arthropathy, patients have short-lived symptoms, i.e., only a few days.
Does the patient have systemic symptoms (beyond the arthritis)?
SLE presents with lung (pleural effusions), kidney (proteinuria and renal failure), CNS (vasculitis, strokes, and change in personality), skin (malar and photosensitivity rash), and hematologic (immune-mediated anemia, thrombocytopenia) manifestations.
Sjögren syndrome has keratoconjunctivitis sicca (dry eyes/mouth) and parotid enlargement. Systemic sclerosis has skin involvement and Raynaud phenomenon.
Wegener granulomatosis presents with upper respiratory (sinusitis and rhinitis), lower respiratory (lung nodules and hemoptysis), and renal (necrotizing glomerulonephritis) involvement.
Is there evidence of joint inflammation?
Evidence of joint inflammation includes joint stiffness in the morning >1 hour, joint erythema and warmth, and elevated erythrocyte sedimentation rate (ESR) and C-reactive protein. RA would produce inflammation, while OA would not.
Do not go further into a history unless you have answered these 4 questions. Examples
A 24-year-old woman presents with bilateral wrist, MCP, PIP joint swelling, and pain
A 32-year-old man presents with knee swelling after you had seen him 1 week ago for left wrist pain and swelling, which has now resolved
A 29-year-old man has right knee pain and swelling and left hip pain
TESTS IN RHEUMATOLOGIC DISEASE
Joint Aspiration
If there is fluid in the joint, it needs immediate analysis. The basic tests to run on the synovial fluid are the 3 Cs (cell count, crystals, and cultures) and the Gram stain.
Synovial fluid may be stratified according to the number of cells:
OA and traumatic arthritis: 200–2,000 WBCs/mm3 in synovial fluid
Inflammatory diseases (RA, gout): 5,000–50,000 WBC/mm3
Septic arthritis: >50,000 WBC/mm3
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
62
Chapter 3 ● Rheumatology
Table 3-1. Synovial Fluid Analysis in Rheumatologic Disease
Disease | WBCs | Crystals/Polarization |
DJD | <2,000 | Negative traumatic |
Inflammatory | 5,000–50,000 | Gout: needle-shaped, negative birefringent Pseudogout (CPPD): rhomboid-shaped, positive birefringent |
Septic | >50,000 | Negative (Gram stain and culture usually negative for GC but positive in Staph, strep, and gram-negatives) |
There are a few exceptions to the above:
Septic arthritis can be present with <50,000 WBC/mm3 in the joint aspirate if antibi- otics are given before the joint aspiration. Consider it if patient has >5,000 WBC/mm3 in the synovial fluid and monoarticular arthritis, but there is an absence of crystals.
Gout and pseudogout uncommonly present with >50,000 WBC/mm3 in the absence of infection. Consider them if there is evidence of crystals in the aspirate.
Culture of joint fluid is positive in only ≤50% of gonococcal arthritis cases.
Antinuclear antibodies (ANAs) are antibodies with the capability to bind to certain structures within a cell nucleus. They are typically found in patients whose immune system is predis- posed to generating antibodies against their own body tissues (called autoimmunity), such as SLE, Sjögren syndrome, and systemic sclerosis. However, they are also found in ~5% of healthy people (though usually in low titers [<1:80]).
The ANA test is performed by exposing the antibodies in the serum of the blood to the laboratory test cells. It is then determined whether there are antibodies that react with various parts of the nucleus. Fluorescent techniques are now often used, thus the test may be referred to as a fluorescent antinuclear antibody test (FANA).
ANAs present in different patterns depending on the staining of the cell nucleus: homoge- neous, speckled, nucleolar, and peripheral (or rim). While these patterns are not specific for any one disease, certain diseases can more frequently be associated with one pattern
or another.
Peripheral (rim) pattern may be seen with SLE
Nucleolar pattern is commonly seen with systemic sclerosis
Speckled pattern is more commonly seen in healthy people
Subsets of ANAs are associated with specific autoimmune diseases and thus used to further diagnose those diseases. For example, anti ds-DNA and anti-SM antibodies are found in patients with SLE; anti-histone antibodies are found in patients with drug-induced lupus.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
63
USMLE Step 2 l Internal Medicine
Clinical Correlate Overall, >95% of SLE patients have positive ANA test results,
making a negative ANA result
a good rule-out test for SLE.
Interpret a positive ANA test in the context of the clinical symptoms:
Positive ANA with no symptoms or abnormal tests is likely to be a false– positive (5% of population)
Positive ANA with arthritis, proteinuria, and pleural effusion is likely to be associated with SLE
Table 3-2. ANA Patterns
Peripheral (Rim) | SLE |
Diffuse | Nonspecific |
Speckled | Nonspecific |
Centromere | CREST |
Nucleolar | Systemic sclerosis |
Table 3-3. Specific ANAs
Anti (native DNA) | SLE only (60%); an indicator of disease activity and lupus nephritis |
Drug-induced lupus (95%) | |
100% mixed connective tissue disease (MCTD) |
Rheumatoid factors (RFs) are autoantibodies against the Fc portion of IgG.
Found in ~70% of patients with RA although they are not specific for RA
Found in 5% of healthy adults (prevalence increases with age, i.e., up to 20% in those age >65)
While RFs are neither sensitive nor specific for the diagnosis of RA, their presence can be of prognostic significance: patients with high titers tend to have more aggressive disease with extraarticular manifestations.
Antineutrophil Cytoplasmic Antibodies
Antineutrophil cytoplasmic antibodies (ANCAs) are antibodies directed against certain proteins in the cytoplasm of neutrophils.
Cytoplasmic (c) ANCA is the diffuse staining pattern observed when serum antibod- ies bind to indicator neutrophils; it is seen in >90% of patients with Wegener granulo- matosis.
Perinuclear (p) ANCA is a localized staining pattern observed on the indicator neutrophils (the major target of these antibodies is the enzyme myeloperoxidase); it is found in PAN and Churg-Strauss but is a nonspecific test.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
64
Chapter 3 ● Rheumatology
Antiphospholipid Antibody Syndrome
Antiphospholipid antibody syndrome (lupus anticoagulant or anticardiolipin antibodies) is a hypercoagulable state associated with a group of antibodies that are directed against phospho- lipids or cardiolipins. It is unclear whether the antibodies are directly involved in the etiology of the clotting disorder associated with this syndrome. The nature of these antibodies causes the common lab abnormalities associated with the syndrome, i.e., elevated partial thrombo- plastin time (PTT) and false-positive RPR or VDRL.
Clinically, it presents with spontaneous abortions in otherwise healthy women or thromboem- bolism (pulmonary embolism, DVT) in other patients. Two first-trimester spontaneous abortions suggest antiphospholipid antibodies.
RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) is a chronic inflammatory multisystemic disease with the main target being the synovium. The hallmark of RA is inflammatory synovitis which presents in a symmetric distribution. The intense joint inflammation that occurs has the potential to destroy cartilage and cause bone erosions and eventually deform the joint.
Anti-CCP (cyclic citrullinated peptide) is also positive in RA and carries a very high specificity. The cause of RA is unknown.
May be triggered as a reaction to an infectious agent (mycoplasma, parvovirus) in a susceptible host
Of the environmental factors, only cigarette smoking seems to be associated with RA
Women affected 3× more than men
Age of onset usually age 35–50 (80%)
An initiation phase of nonspecific inflammation occurs, followed by an amplification phase resulting from T-cell activation, and finally the stage of chronic inflammation and tissue injury.
The predominant infiltrating cell is the T lymphocyte. Diseases such as HIV, where T cells are decreased, will characteristically improve preexisting RA; this also explains why RA is very rare in patients with HIV.
Recent studies have shown that excessive amounts of the pro-inflammatory cytokines—tumor necrosis factor alpha (TNF-a), interleukin-1, and interleukin-6 (IL-6)—mediate most of the pathogenic features of RA. This underscores the focus of new treatment modalities on inhibit- ing these cytokines (see TNF inhibitors on following pages).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
65
USMLE Step 2 l Internal Medicine
Note
In 2010, new criteria for RA were proposed by the American College of Rheumatology and European League against Rheumatism focusing more on serologies, acute phase reactants, number of joints involved, and duration of joint involvement over 6 weeks. This leads to a point system.
For the moment, the 1987 criteria are not obsolete.
Clinical Presentation. Required for a diagnosis of RA are 4 of the following diagnostic criteria:
Morning stiffness (>1 h) for 6 weeks
Swelling of wrists, MCPs, PIPs for 6 weeks
Swelling of 3 joints for 6 weeks
Symmetric joint swelling for 6 weeks
RF positive or anti-cyclic citrullinated peptide
CRP or ESR
ray abnormalities and nodules are not needed for a diagnosis of RA.
Criteria. RA is a chronic inflammatory symmetric arthropathy. There needs to be involve- ment of multiple joints, but some joints are never involved in RA:
Because RA is a systemic disease, ~70% of patients present with constitutional symptoms—fa- tigue, anorexia, weight loss, generalized weakness—before the onset of the arthritis.
Caplan syndrome (RA + pneumoconiosis)
Laboratory Findings. RF or anti-CCP; anemia; ESR or C-reactive protein (CRP); x-rays; synovial fluid analysis
Diagnosis. The diagnosis is based on the use of clinical criteria; there is no single test or finding that will diagnose RA. Anti-CCP is more specific than RF.
Treatment. None of the nonsteroidal antiinflammatory drugs (NSAIDs) have been shown to be better than aspirin in RA, but they have fewer GI side effects.
There is no single NSAID superior to other agents, and the newer agents have not been shown to have a decreased incidence in toxicity (GI, renal, etc.).
Cyclooxygenase 2 (COX-2) inhibitors are a type of NSAID which selectively blocks the COX-2 enzyme at the site of inflammation. The benefit of COX-2 inhibitors is that they do not inhibit COX-1, an enzyme that helps with the production of the protective stomach lining. The nonselective (traditional) types of NSAIDs block both COX-2 and COX-1, which can lead to increased risk for GI side effects (bleeding, etc.).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
66
Chapter 3 ● Rheumatology
Because of the increased risk of MI, both rofecoxib and valdecoxib have been recalled; currently only celecoxib is available.
Other drugs used in RA:
Glucocorticoids (usually for short courses only)
Disease-modifying agents: antimalarials, gold, sulfasalazine, methotrexate (MTX), and tumor necrosis factor (TNF) receptor inhibitors
Disease-Modifying Anti-Rheumatic Drugs
The best initial DMARD is methotrexate (MTX). If MTX does not control disease, an anti- TNF medication is added to treatment.
Table 3-4. Adverse Effects of DMARD
Drug | ||
Hydroxychloroquine | ||
MTX (methotrexate; most | ||
of treatment) | ||
Hydroxychloroquine and sulfasalazine are used in early, mild disease. Steroids are used briefly to control disease while waiting for methotrexate to work.
Biologic Agents. Tumor necrosis factor (TNF) inhibitors. Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine produced by macrophages and lymphocytes. It is found in large quantities in the rheumatoid joint and is produced locally in the joint by
synovial macrophages and lymphocytes infiltrating the joint synovium. TNF inhibitors relieve the signs and symptoms of RA, and slow or halt radiographic damage. These drugs have been shown to be effective in patients who were thought to be resistant to all methotrexate.
Latent assessment and treatment for TB are required before use of any of these agents. There are 3 TNF inhibitors approved for the treatment of RA:
Infliximab (Remicade) is a monoclonal antibody to TNF-α that binds to TNF-α in the joint and in the circulation. The combination of infliximab and methotrexate is very effective in reducing clinical manifestations of disease. Infliximab is given as an IV infusion. Cases of sepsis, disseminated tuberculosis, and other opportunistic infec- tions have been reported for patients treated with infliximab or other anti-TNF therapy.
Adalimumab (Humira) is an anti-TNF mAb that differs from infliximab in that its sequences are entirely human.
Etanercept (Enbrel) is a human fusion protein that is entirely human, and anti-etaner- cept antibodies are relatively uncommon.
Complications/Follow-Up. Aggressive disease is likely to occur with the following features: high titers of RF, diffuse rheumatoid nodules, early joint erosions, late age of onset, and certain subtypes of the HLA-DR4.
Note
Screen for TB before using TNF inhibitors.
Clinical Pearl
Consider atlantoaxial subluxation in patients with RA who complain of occipital headaches and upper extremity tingling and numbness.
Always rule out subclinical subluxation in patients with RA who are undergoing surgery and intubation electively.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
67
USMLE Step 2 l Internal Medicine
Atlantoaxial subluxation may occur in patients with RA when there is excessive movement at the junction between the atlas (C1) and axis (C2), due to a bony or ligamentous abnormality. In RA, the incidence of cervical involvement has been reported to be 25–80% and results from pannus formation at the synovial joints between C1 and C2. Neurologic symptoms occur when the spinal cord is involved (paraplegia, quadriplegia). Commonly, patients have subtle symp- toms, which include neck pain (occipital), C2 radicular pain (paresthesias of the hands and feet), and myelopathy.
Consider this diagnosis in patients who have RA and neck pain, paresthesias, etc. The first test to do when considering the diagnosis is an x-ray of the cervical spine (order multiple views of the cervical spine, including an open-mouth view). You may further investigate with a CT scan or an MRI. Refer always to a spine surgeon (orthopedic specialist or neuro- surgeon) if the radiologic testing is positive. All patients with RA should be screened with a plain x-ray for C1–C2 subluxation before intubation or anesthesia is performed.
If a patient with RA presents with a swollen painful calf, consider a ruptured Baker cyst. Baker cyst is the extension of inflamed synovium into the popliteal space.
A 39-year-old woman presents to the outpatient clinic with pain and stiffness in her hands and wrists for the past 6 weeks. She is diagnosed with rheumatoid arthritis, although there is no evidence of erosion on x-ray. Which of the following is the management of choice at this time?
Answer: A
A 35-year-old woman is brought for the evaluation of confusion lasting 1 day. Her friends and family inform you that “she did not know how to come home from work” and that lately “she has not been herself.” You find that the patient has elevated blood pressure, decreased air entry on the right lung base with dullness to percussion, and symmetrical joint swelling of the wrists and MCPs. Chemistry profile shows elevated creatinine 2.4 mg/dL and protein in the urine on the urinalysis.
Systemic lupus erythematosus (SLE) is a systemic disease in which tissues and multiple organs are damaged by pathogenic autoantibodies and immune complexes. Etiology is unknown.
Ninety percent of cases are women.
The abnormal immune response probably depends on interactions between a suscep- tible host and environmental factors. Ultraviolet (UV)-B light is the only environ- mental factor known to cause flares.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
68
Chapter 3 ● Rheumatology
Clinical Presentation. Required for a diagnosis of SLE are 4 of the following diagnostic criteria:
Malar rash
Discoid rash
Photosensitivity
Oral ulcers
Arthritis
Serositis (pleuritis or pericarditis)
Renal involvement
Neurologic disorder (seizures or psychosis)
Hematologic disorder (hemolytic anemia, leukopenia, thrombocytopenia)
Immunologic disorder (anti-dsDNA, anti-SM, and other ANAs)
Summary of Criteria
Arthritis is identical to that of RA except that it is non-erosive.
Both the malar rash and photosensitivity rash (diffuse, maculopapular) flare with exposure to UV-B light (thus are considered photosensitive) and resolve with no scarring of the skin. The discoid lupus (DLE) is a circular rash with a raised rim that occurs over the scalp and face; it can be disfiguring because of central atrophy and scarring. Only 5% of patients with DLE will go on to develop SLE.
All patients with renal involvement must undergo renal biopsy before treatment is initiated.
Change of personality and psychosis may be manifestations of CNS lupus. Seizures, paralysis, and aphasia may follow.
Libman-Sacks endocarditis is a noninfectious endocarditis that is occasionally seen in lupus patients.
Diagnosis. A positive ANA supports the diagnosis but is not specific for SLE. Complement levels (C3, C4) are decreased in those with active lupus, as are elevated levels of ds-DNA antibodies.
Treatment. There is no cure; treat to control symptoms.
NSAIDs are used to treat arthritis and pleurisy.
Corticosteroid creams are used to treat skin rash; antimalaria drugs (hydroxychloro- quine) and oral corticosteroids may also be used for skin and arthritic symptoms.
Cytotoxic drugs (azathioprine, cyclophosphamide) are used for severe symptoms (lupus nephritis, heart and lung involvement, hemolytic anemia, CNS involvement), along with corticosteroids.
Mycophenolate is often used to treat lupus nephritis.
All patients should be advised to wear protective clothing, sunglasses, and sunscreen when in the sun. Belimumab is an inhibitor of B-cell activation; it is an IgG monoclonal antibody given intravenously to prevent B-cell activation.
Prognosis. The prognosis of patients with SLE has improved significantly in recent years with a 10-year survival rate >85%. People with severe involvement of the CNS, kidney, heart, and
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
69
USMLE Step 2 l Internal Medicine
lungs have a worse prognosis in terms of overall survival and disability. Lupus nephritis is probably the most common cause of disability in patients with SLE.
Note the following with respect to SLE and pregnancy:
Fertility rates are normal in patients with SLE, but spontaneous abortion and stillbirth are more common when compared with healthy patients; one reason for the spontane- ous abortion may be anti-phospholipid antibodies, which cause placental infarcts. This is treated with low-molecular weight heparin (LMWH) during pregnancy.
It is unclear whether lupus worsens with pregnancy. In the case of a lupus flare during pregnancy, steroids may be used safely to suppress the disease.
All pregnant patients with lupus need to be screened for SSA/anti-Ro antibodies. These antibodies cross the placenta and are passively transferred to the fetus, causing neonatal lupus and heart block.
Drug-induced lupus erythematosus is a side effect of certain medications. Over 40 drugs have been implicated to cause drug-induced lupus, but the most common are hydralazine, isonia- zid, procainamide, and quinidine. Symptoms typically include arthritis, fatigue, fever, and pleurisy (rare).
Acute onset SLE is usually not confused with drug-induced lupus, due to the lack of skin disease, kidney disease, and milder symptoms seen in the latter. Also, photosensitivity, hair loss, and CNS disease are uncommon in drug-induced lupus.
Patients with drug-induced lupus develop ANAs, although those with drug-induced lupus related to quinidine often are ANA-negative. The ANAs in drug-induced lupus are autoanti- bodies that react with a histone-DNA complex, which is the major component of the nucleus (anti-histone antibodies).
Anti-histone antibody testing is a sensitive marker for the diagnosis of drug-induced lupus. Hydralazine is the exception, as only 35% of patients will have positive anti-histone antibodies.
Once the suspected medication is stopped, symptoms resolve in 1–2 weeks. This confirms with certainty the diagnosis of drug-induced lupus.
SCLERODERMA
A 36-year-old woman presents with skin tightness and painful fingertips with exposure to cold for >1 year. Physical examination reveals blood pressure 165/100 mm Hg and diffuse shiny, thickened skin. Lab tests reveal elevated serum creatinine. The examination is otherwise normal.
Systemic sclerosis (SSc) is a chronic multisystem disease characterized clinically by thickening of the skin caused by accumulation of connective tissue and by involvement of visceral organs (GI, lungs, kidneys).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
70
Chapter 3 ● Rheumatology
Clinical Presentation. All patients with SSc have skin thickening and Raynaud phenomenon (due to vascular damage and diminished blood flow to the extremities).
GI: esophageal dysmotility; hypomotility of small intestine with bacterial overgrowth and malabsorption; dilatation of large intestine with formation of large diverticula
Pulmonary: pulmonary fibrosis with restrictive lung disease and cor pulmonale (pulmonary involvement is now the leading cause of death in SSc)
Renal: scleroderma renal crisis in which malignant hypertension develops and causes acute renal failure (had been leading cause of death but is now easily treated with ACE inhibitors)
Scleroderma renal crisis has been used to characterize the renal involvement in scleroderma, where malignant hypertension occurs over days to weeks and is associated with acute renal failure (rapid rise in creatinine and proteinuria). ACE inhibitors (enalapril, lisinopril) have been effective at reducing the devastating consequences of renal crisis in patients where treatment is initiated before the onset of renal failure.
Copyright 2007 CMSP—Custom Medical Stock Photo.
Figure 3-1. Shiny Skin of Scleroderma
CREST syndrome, a variant of scleroderma, is now called limited scleroderma or limited cutaneous systemic sclerosis. The acronym CREST represents the hallmarks of the disease:
Calcinosis (a condition in which calcium deposits occur in soft tissues, usually fingers (especially PIP joints), knees, and elbows; deposits occur near skin surface and may ulcerate and become infected)
Raynaud
Esophageal dysfunction
Sclerodactyly (skin thickening, primarily affecting fingers and toes)
Telangiectasias
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
71
USMLE Step 2 l Internal Medicine
Note
All of the diseases we just reviewed have an arthritis that is symmetric and polyarticular. RA is a disease that involves mostly the joints; the others (SLE, SSc, and Sjögren) usually have arthritis plus multiple organ involvement.
(Note that parvovirus B19 and hepatitis B may also cause symmetrical polyarthropathy.)
Limited scleroderma generally has the following features:
Skin involvement that does not extend above the elbow or above the knee (rarely, the face may be affected)
Slow progression, as compared with the diffuse cutaneous form of scleroderma, which is more likely to affect internal organs
Pulmonary arterial hypertension (25–50% of patients)
Interstitial lung disease (10% of patients)
Positive ANA test, showing a pattern of anticentromere antibodies (up to 90% of patients)
Negative antibodies to Scl-70, as compared with positive antibodies to Scl-70 with diffuse scleroderma
Raynaud phenomenon is defined as episodes of pallor or cyanosis in response to cold or emotional stimuli. The pallor is caused by vasoconstriction of blood vessels (arteries and arte- rioles) that results in reduced blood flow, while cyanosis is created by deoxygenation of slow- flowing blood. After rewarming the hands, the blood flow will rebound (hyperemia) and the skin will appear reddened or blushed.
Patients commonly complain of cold sensitivity and involvement of other areas of the skin, including the ears, nose, and lower extremities.
Episodes come as sudden attacks and are most often triggered by rapid changes in ambient temperature; attacks may begin in 1 or 2 fingers but typically involve all fingers and/or toes symmetrically and bilaterally.
In primary Raynaud phenomenon (Raynaud disease), the patient has no associated underlying disease. In secondary Raynaud phenomenon, the patient has a defined secondary or associated disease (e.g., scleroderma). To differentiate them, do a nailfold capillaroscopy test (place a drop of oil on patient’s nailfold at the base of the fingernail) and examine that area under a microscope for any capillary changes. Enlarged, dilated, or absent nailfold capillaries are noted among patients with scleroderma and other autoimmune diseases.
About 5% of the general population has symptoms and signs consistent with Raynaud phe- nomenon. It is more common among young women, about 30% have a first-degree relative with Raynaud, and most have primary Raynaud phenomenon without any defined cause or associated systemic disease.
Treatment. There is no cure for SSc. For the skin manifestations, use D-penicillamine. For severe Raynaud phenomenon, use calcium-channel blockers, specifically nifedipine. For hypertension, use ACE inhibitors.
SJÖGREN SYNDROME
A 42-year-old woman presents with some peculiar symptoms lasting 1 year. She feels there is constantly something in her eyes–like dust or sand–and that dry and solid foods are painful to swallow. You are perplexed by her complaints but decide to examine her and find that she has bilateral parotid enlargement The exam is otherwise unremarkable. ANA test is positive. What specific ANAs would you expect to be positive in this patient?
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
72
Chapter 3 ● Rheumatology
Sjögren syndrome is a chronic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands, resulting in xerostomia and dry eyes. It may be seen alone (primary) or with other autoimmune diseases (secondary) such as RA, primary biliary cirrhosis, or SLE. As the syndrome progresses, it becomes a systemic disease involving major organs (lungs, kidneys, etc.) and may eventually evolve into a lymphoproliferative disease—malignant lymphoma.
Clinical Presentation.
Itchy eyes, with a “sandy feeling” under the eyes due to reduced lacrimal production and destruction of the corneal epithelium—keratoconjunctivitis sicca
Difficulty swallowing food
Possible increase in dental caries
Possible parotid enlargement
Schirmer’s test will show decreased tear production, and rose bengal stain will document corneal ulcerations
ANAs will be positive and specifically anti-Ro (SSA) and anti-La (SSB)
Lymphocytic infiltration of the salivary glands will be noted on biopsy
Treatment. Treatment is symptomatic only. Use artificial tears. Pilocarpine and cevimeline increase acetylcholine and increase tear and saliva production.
Clinical Recall
A 24-year-old woman is recently diagnosed with systemic lupus erythematosus. Which of the following would be appropriate counseling at the time of diagnosis?
The patient should use sunscreen whenever outdoors to avoid flare- ups
The patient has a higher than normal chance of spontaneous abortion if she becomes pregnant
Prognosis is based on the severity and evolution of the disease
All of the above
Answer: E
SERONEGATIVE ARTHROPATHIES, SPONDYLOARTHROPATHIES
A 27-year-old man presents with complaints of severe lower back stiffness and pain that have been bothering him for the past 5 years. The stiffness is most apparent in the morning when he wakes up, lasting sometimes >2 h. The only thing improving these problems is exercise. On examination there is 2/6 murmur over the second right intercostal space and decreased range-of-motion of the lumbar spine.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
73
USMLE Step 2 l Internal Medicine
The spondyloarthropathies are a group of disorders that share certain clinical features and an association with the B-27 allele. Their similarities suggest that these disorders share pathogenic mechanisms.
There are 4 diseases that have similar clinical and laboratory characteristics:
Table 3-5. Seronegative Arthropathies
Disease | Characteristics |
Ankylosing spondylitis | |
Reactive arthritis | |
Psoriatic arthritis | |
Enteropathic arthropathy |
Seronegative (ANA negative, RF negative)
Involve lower back and sacroiliac joints
HLA-B27
Extraarticular manifestations
All of the diseases have most of the 4 characteristics, plus a few others that are disease-specific.
Ankylosing spondylitis (AS) is an inflammatory disorder that affects primarily the axial skeleton and peripheral joints. Etiology is unknown.
Men > women by 3–4x (this is one of the few collagen vascular diseases that affects men more than women
90% of patients are positive for HLA B-27
Clinical Presentation. AS will usually present with chronic lower back pain in a young man (in his late twenties to early thirties). The giveaway is the morning stiffness lasting at least 1 h that improves with exercise.
Extraarticular manifestations (common): anterior uveitis, aortic insufficiency some- times leading to CHF and third-degree heart block
– Because of this, spine fracture can be seen in AS patients after minimal trauma (know that spine fractures occur with insignificant stress in older people with osteoporosis and young people with long-standing inflammatory disease of the spine, e.g., AS)
Cervical spine is rarely, if ever, affected and only late in the disease
X-ray shows evidence of sacroiliitis (earliest finding) and eventual fusing of the sacroiliac joint; chronic spine inflammation will eventually cause bamboo spine and squaring of vertebral bodies
Diagnosis is based on clinical and x-ray findings. The HLA-B27 is not commonly used as a diagnostic test.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
74
Chapter 3 ● Rheumatology
SIU BIOMED COMM 2007—Custom Medical Stock Photo.
Figure 3-2. X-ray of Pelvis in AS Demonstrating Sacroiliitis
Treatment. Treat with NSAIDs, physical therapy, and exercise. The most promising medica- tions for AS and other spondyloarthropathies are the TNF blockers (infliximab, adalimumab, etanercept). These biologic agents are recommended for axial disease.
Unlike RA, anti-TNF medications are used first and methotrexate used later. Anti-TNF drugs work better for axial disease.
Reactive Arthritis
Reactive arthritis (ReA) is a seronegative arthropathy that occurs as a complication from an infection somewhere in the body. There are 2 types of infections causing different syndromes.
One (Reiter syndrome) occurs after a nongonococcal urethritis (chlamydia, urea- plasma). These patients have distinct mucocutaneous manifestations: keratoderma blennorrhagica, circinate balanitis, oral or genital ulcers, conjunctivitis, and arthritis.
The other ReA occurs after an infectious diarrhea caused by Campylobacter, Shigella, or Salmonella organisms (think of the organisms that cause enteroinvasive diarrheas; these are the same ones that cause ReA). The most common is Campylobacter.
Diagnosis is based on clinical criteria. X-ray findings will be consistent with a seronegative spondyloarthropathy.
Treatment. Treatment is the same as for AS. There are studies that support an accelerated recovery of Reiter syndrome caused by a chlamydial infection from prolonged tetracycline use (~3 weeks’ duration). There are also studies to support the notion that prompt antibiotic use in urethritis will decrease the chance of Reiter syndrome (this is the only exception to the rule that the seronegative arthropathies are untreatable diseases).
A severe form of Reiter syndrome and reactive arthritis has been described in HIV patients. The skin manifestations are particularly aggressive in these patients and improve with antiret- roviral medications.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
75
USMLE Step 2 l Internal Medicine
phil.cdc.gov.
Figure 3-3. Keratoderma Blennorrhagica Seen with Reiter Syndrome
Psoriatic arthritis commonly involves the DIP joints when associated with psoriatic nail disease (pitting of the nails); this involvement may sometimes cause the characteristic sausage-shaped digit. Here, the peripheral arthritis is deforming.
Enteropathic arthropathy occurs with UC and Crohn’s disease; sometimes the arthritis occurs with flares of the IBD. Patients may develop characteristic skin lesions: pyoderma gangreno- sum and erythema nodosum.
Wikipedia, James Heilman, MD
Figure 3-4. Erythema Nodosum, Characteristic of Some Rheumatic Disorders
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
76
Chapter 3 ● Rheumatology
OSTEOARTHRITIS
A 64-year-old man presents with knee pain. He tells you that he has had right knee pain for many years but it has recently gotten worse. He denies constitutional symptoms and other joint pain except for his left second and third DIPs. He has not noticed stiffness in the morning. On examination crepitations are heard as you move the right knee, but otherwise there is no evidence of swelling, warmth, or erythema of the knee. Laboratory testing is unremarkable.
Osteoarthritis (OA) is the most common joint disease in humans; the target tissue is articular cartilage. There is destruction of cartilage along with secondary remodeling and hypertrophy of the bone. Unlike RA, OA is not an inflammatory disease.
Knee OA is the leading cause of chronic disability in the elderly.
Major risk factors for OA include age, female sex, genetic factors, major joint trauma, repetitive stress, and obesity.
Classification: idiopathic (most common form) where no predisposing factor is evident, and secondary, where there is an underlying cause, e.g., another arthropathiesy (gout), endocrine disease (DM, acromegaly), deposition diseases (hemochromatosis), and mechanical factors (valgus or varus deformity, unequal lower extremity length).
Any disease that causes stress or trauma to a joint may eventually cause secondary OA.
Idiopathic OA and secondary OA are pathologically indistinguishable.
The most common joint affected by OA is the knee, and the second most common is the base of the thumb.
Clinical Presentation. The major joints involved in OA are the weight-bearing joints (hip and knee) and the small joints of the fingers (PIPs and DIPs). These joints are affected in an oligoartic- ular-asymmetric or monoarticular pattern. The joint involvement is very slow, progressive, and irreversible. Because the cartilage fails and there is increased pressure on articular bone, joint pain increases with exercise and is relieved by rest. Morning stiffness is always <20–30 min. Crepitations may be noted with movement of the joint. There are no systemic manifestations in OA.
Lab tests are always normal, especially indices of inflammation.
Thus, ESR and C-reactive protein are always normal. (If ESR is elevated, some other process is complicating OA, e.g., septic joint, or it is not OA.)
X-ray findings include osteophytes and unequal joint space.
Osteophytes (spurs) are the reparative efforts by the bone; when these occur in the PIPs they are called Bouchard’s nodes, whereas similar changes occurring in the DIPs are called Heberden’s nodes.
Diagnosis is made with clinical and x-ray findings.
Treatment. There is no cure for OA, so focus on maintaining mobility and reducing pain. Therapy is palliative because no agent has been shown to change the natural course of the disease.
Reduce joint loading with correction of poor posture and weight loss.
Design physical therapy and exercise programs which maintain range of motion, strengthen periarticular muscles, and improve physical fitness.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
77
USMLE Step 2 l Internal Medicine
Note
There are rare cases of erosive OA, polyarticular OA, and OA with inflammatory features.
You will not need to know them for the exam.
Use NSAIDs only to alleviate pain (chondroprotective effect of certain NSAIDs has not been proven). In double-blinded placebo trials, there was no difference in relief of joint pain among acetaminophen (4,000 mg/d), analgesic doses of ibuprofen (1,200 mg/d), and antiinflammatory doses of ibuprofen (2,400 mg/d).
Use acetaminophen as the first drug to use for pain in OA. However, it is reasonable to add analgesic doses of NSAIDs if there is no relief. Use cautious dosing with the elderly because they are at highest risk for the side effects associated with NSAIDs, especially GI (ulcers, hemorrhage, etc.). Consider COX-2 inhibitors for those at high risk for GI complications (only available agent is celecoxib).
Use capsaicin cream, which depletes local sensory nerve endings of substance P. Some patients do feel local burning.
Perform orthopedic surgery and joint arthroplasty only when aggressive medical treatment has been unsatisfactory, especially if the patient’s quality of life has been decreased.
Which of the following is a major risk for osteoarthritis?
Answer: E
CRYSTAL-INDUCED ARTHROPATHIES
The crystal-induced arthropathies—monosodium urate (MSU), calcium pyrophosphate (CPPD), calcium oxalate (CaOx), and calcium hydroxyapatite (HA)— are caused by micro- crystal deposition in joints. In spite of differences in crystal morphology, they have identical clinical presentations and can be distinguished only by synovial fluid analysis.
Gout
Gout is a type of inflammatory arthritis which develops as a result of high levels of uric acid in the blood. It affects mostly middle-aged men (85%), but women become increasingly suscep- tible to gout after menopause.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
78
Chapter 3 ● Rheumatology
Gout presents most commonly with acute monoarthritis. As gout becomes chronic, multiple joints may be involved, and deposition of urate crystals in connective tissue (tophi) and kid- neys may occur.
Metatarsophalangeal joint of the first toe is commonly affected (podagra), but other joints such as the knee, ankle, PIPs, or DIPs may be initially involved
First episode often occurs at night with severe joint pain waking the patient from sleep; the joint rapidly becomes warm, red, and tender (it looks exactly like cellulitis)
Without treatment the joint pain goes away spontaneously within 3–14 days
Certain events can precipitate gout: excessive alcohol ingestion, red meat intake, trauma, surgery, infection, steroid withdrawal, drugs (diuretics such as hydrochlorothiazide and furosemide; anti-TB medications such as pyrazinamide and ethambutol), or serious medical illness.
MSU deposition causes an intense inflammatory process—red, warm joint.
Diagnosis. Serum uric acid level is of no value in the diagnosis of acute urate arthropathy. During an acute attack, serum uric acid may be normal or low, but many people with elevated serum uric acid never develop gout. Diagnosis is made by analysis of synovial fluid instead. On synovial fluid analysis, the MSU crystals are negative birefringent and needle-shaped. WBCs will range 5000–50,000. X-ray of a joint that has been involved in multiple gouty attacks will show erosive calcifications.
Treatment. With acute gouty arthritis, the goal is to decrease inflammation and thus prevent erosion and joint destruction; also in this stage it is very important to avoid fluctuations in serum uric acid level.
NSAIDs
Steroids oral (rarely intraarticular) in elderly patients who cannot tolerate NSAIDs/ colchicine or in patients with renal impairment
Colchicine is rarely to be used in acute gout but is still available.
With chronic hypouricemic gout, the goal is to decrease uric acid levels. This is usually required for life and initiated in those whose recurrent gouty attacks cannot be corrected by low-purine diet, alcohol limitation, avoiding diuretics, etc. Unlike acute gout, the uric acid level here may help the physician to follow the effect of hypouricemic treatment.
Allopurinol can be used in overproducers, undersecretors, or patients with renal failure or kidney stones
Febuxostat is used in those intolerant of allopurinol.
Pegloticase dissolves uric acid: used in refractory disease
Probenecid can be used in the undersecretors (>80% of adults) only. Rarely used today. Consider the following scenario.
A 32-year-old man comes with a history of right ankle swelling that occurred the night before. He has noticed that his ankle has been red, warm, and very painful. He occasionally drinks alcohol. On examination a red swollen ankle is noted with evidence of an effusion. Range of motion is restricted.
Note
Do not initiate allopurinol during an acute crisis of gout. However, if a patient has been taking allopurinol and an acute attack occurs, do not discontinue.
Clinical Pearl
Use primarily allopurinol in the chronic treatment of gout.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
79
USMLE Step 2 l Internal Medicine
Clinical Pearl
Always investigate patients with pseudogout for systemic disease, especially hemochromatosis.
The first step with this patient is aspiration. After confirming the diagnosis, treat with NSAIDs.
Six months later, the patient returns with left knee swelling. On examination a red warm knee is noted.
The first step now is aspiration. After confirming the diagnosis, treat with NSAIDs.
On a routine visit the same patient has had 4 documented episodes of gout, despite limiting alcohol and diet.
Now the next step is to consider allopurinol or probenecid.
You decide to place the patient on allopurinol. He does very well for 2 years with no gouty attacks. After that he then experiences another episode of right ankle swelling.
CPPD crystal deposition is more common in elderly and in those with preexisting joint damage. A small percentage of the patients have metabolic abnormalities that are associated with CPPD deposition (secondary).
Remember the 4 Hs. The presence of pseudogout in a patient age <50 should raise suspicions about one of these metabolic abnormalities.
Possible acute presentation like gout, or possible asymptomatic and chronic form
Knee is most commonly affected joint; other joints commonly affected are the wrist, shoulder, and ankle
Definitive diagnosis requires the typical rectangular, rhomboid, positive birefringent crystals on synovial fluid evaluation. X-ray may reveal linear radiodense deposits in joint menisci or articular cartilage (chondrocalcinosis).
Treatment. Treat as you would treat gout. Low doses of colchicine may be considered to prevent frequent recurrences.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
80
Chapter 3 ● Rheumatology
SEPTIC ARTHRITIS
A 67-year-old woman with history of RA for many years presents with right shoulder pain and swelling for 2 days. She has low-grade fever. Examination reveals decreased passive and active range of motion of the right shoulder joint, as well as erythema. She asks you if this is related to an RA flare and if she should start steroids to decrease the pain.
The first step would be to do an arthrocentesis.
The most common cause of infectious arthritis is gonorrhea, and gonococcal arthritis accounts for 70% of episodes in patients age <40. Women are at greater risk during menses and preg- nancy, and women 2–3x more likely than men to develop disseminated arthritis.
In older patients, Staphylococcus aureus is a common cause of infectious arthritis and occurs in patients with preexisting joint destruction from other rheumatic diseases. Patients with RA have the highest risk because of chronic inflamed or destroyed joints, steroid therapy, and frequent skin breakdown over deformed joints.
Acute bacterial infection may cause rapid cartilage destruction, and thus a patient presenting with monoarticular arthritis needs prompt diagnosis. This is done by arthrocentesis. Further, Staph or Strep must be cleaned out of the joint space by arthrocentesis or arthroscopy.
Remember that most infected joints with gonococcal will not have positive cultures, and the Gram stain will be negative.
Treatment. Treatment should focus on the likely etiology. A 30-year-old woman with acute monoarticular arthritis who has >50,000 WBCs in the synovial fluid without crystals should be treated with ceftriaxone. A 72-year-old man with RA with the same findings should be treated with nafcillin or vancomycin.
This disease is discussed further in the Infectious Diseases chapter.
Vasculitis is an inflammatory process involving the blood vessels, resulting in a decrease of the lumen diameter and eventual ischemia of the tissues supplied. The vasculitis syndromes are stratified according to the types of vessels involved.
Wegener Granulomatosis
Wegener granulomatosis is a small vessel vasculitis. It typically affects the respiratory tract (sinuses, nose, trachea, and lungs) and kidneys, but can involve any organ system.
The most common sign of Wegener granulomatosis is involvement of the upper respiratory tract, which occurs in nearly all patients. Symptoms include rhinitis, sinusitis, and, rarely, nasal ulcers.
A common sign of the disease is chronic rhinitis that does not respond to usual treatment and that becomes increasingly worse.
Despite lack of symptoms, lungs are affected in most people; if symptoms are present, they include cough, hemoptysis, and dyspnea.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
81
USMLE Step 2 l Internal Medicine
Clinical Pearl
In patients with PAN, exclude co-existing chronic active viral hepatitis.
Note
To help remember Churg- Strauss syndrome, think of it as PAN in an asthmatic patient.
Kidney involvement (>80% of patients) (major cause of morbidity and mortality)
Arthritis (60% of patients)
Presence of antineutrophil cytoplasmic antibodies (C-ANCA)
Although a positive ANCA test is useful to support a suspected diagnosis of Wegener granulomatosis, it is never diagnostic.
The C-ANCA test may be negative in some people with active Wegener. The only way to confirm the diagnosis is with a biopsy of an involved organ (usually nasal septum), demonstrating the presence of vasculitis and granulomas.
Standard treatment is combined glucocorticoid plus an immunosuppressive agent (cyclophosphamide). In a study of 158 patients who were treated with prednisone and cyclophosphamide at the National Institutes of Health (NIH), 90% markedly improved; after years of follow-up, 80% of the patients survived.
Polyarteritis nodosa (PAN) is a multisystem disease which presents with nonspecific com- plaints such as fever, malaise, weight loss, anorexia, and abdominal pain. The disease can affect nearly any site in the body, except the lungs. It has a predisposition for organs such as the skin, kidney, nerves, and GI tract.
GI manifestations are common: abdominal pain and GI bleed (occasionally mistaken for inflammatory bowel disease).
Active hepatitis B infection is seen in a minority of patients.
Diagnosis is made by biopsy of involved organs (most commonly taken from skin, symptom- atic nerves, or muscle). The biopsy will show pathologic changes in medium-size arteries.
Angiogram of the abdominal vessels may also be helpful for diagnosing PAN, since aneurysms affecting the arteries of the kidneys and/or GI tract are found.
Treatment is high doses of corticosteroids and immunosuppressive drugs (cyclophosphamide). (Before these treatments were available, untreated PAN was usually fatal within weeks to months, with most deaths occurring from kidney failure, or heart or GI complications.)
Churg-Strauss Syndrome
Churg-Strauss syndrome shares many of the clinical and pathologic features of PAN; both involve the small- and medium-sized arteries. Any organ can be involved.
The cardinal manifestations of Churg-Strauss are asthma, eosinophilia, and lung involvement. The typical patient is middle-aged, with new-onset asthma. Asthma symptoms may begin long before the onset of vasculitis. Other symptoms include mononeuropathy (mononeuritis multiplex similar to PAN), transient pulmonary infiltrates on chest x-ray, paranasal sinus abnormalities, nasal polyps, and allergic rhinitis.
Diagnosis is made by biopsy. Treatment is similar to PAN (combination of prednisone and cytotoxic agent).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
82
Chapter 3 ● Rheumatology
Temporal Arteritis
Temporal arteritis (TA) (also known as giant cell arteritis), is a vasculitis affecting the large arteries that supply the head, eyes, and optic nerves. New-onset headache in any patient age
>50 prompts consideration of this diagnosis, which if left untreated may result in permanent vision loss. Symptoms include:
Headache and pain in one or both temples (most common symptoms)
Scalp tenderness (pain when combing hair)
Jaw claudication (jaw pain when chewing)
Decreased vision or blurry vision
Tongue numbness
Sudden loss of vision (rare)
Proximal stiffness (neck, arms, hips) due to polymyalgia rheumatica, a coexisting condition (seen in >25% of patients with TA)
Erythrocyte sedimentation test (ESR) is always increased in TA, i.e., all patients will have elevated ESR (100% sensitive). Therefore, the first test to do when TA is suspected is ESR. Diagnosis is confirmed by biopsy of the temporal arteries, which will demonstrate the characteristic giant cells. When TA is suspected and ESR is elevated, start corticosteroids immediately, before the temporal artery biopsy is performed. Do not withhold treatment waiting for the biopsy to be done.
The first step is to do an ESR; if elevated, start prednisone.
A 42-year-old woman is admitted to your service with severe proximal weakness for 2 months. Examination shows a diffuse lilac rash over the sun-exposed areas. Motor strength is 3/5 in the upper and lower proximal muscle groups.
The inflammatory myopathies are inflammatory muscle diseases that present with progressive muscle weakness. They include polymyositis, dermatomyositis, and inclusion body myositis.
Patients report difficulty with tasks that involve the proximal muscles: lifting objects, combing hair, getting up from a chair.
Fine-motor tasks that involve the distal muscles, e.g., writing, are affected only late in the disease.
Ocular muscles are never involved (this feature differentiates the inflammatory myopathies from myasthenia gravis and Eaton-Lambert syndrome).
Clinical Pearl
Always consider TA in patients with new-onset headache who are age >50–60.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
83
USMLE Step 2 l Internal Medicine
Dermatomyositis will also have skin involvement; the heliotrope rash is a purple-lilac discoloration of the face, eyelids, and sun-exposed areas of the body. Gottron’s papules are the scaly lesions seen sometimes over the knuckles.
Laboratory Findings. The inflammatory destruction of muscles causes elevated muscle enzymes (sometimes up to 50-fold), creatine phosphokinase (CPK), and aldolase. These are the most sensitive tests to perform in patients suspected of an inflammatory myopathy.
Autoantibodies (anti-Jo-1) occur in patients with inflammatory myopathies, supporting a possible autoimmune origin.
Diagnosis. Electromyography shows evidence of myopathic potentials characterized by short-duration, low-amplitude units. Diagnosis is confirmed by muscle biopsy.
Treatment. For polymyositis and dermatomyositis, steroids are useful. Inclusion body myositis is resistant to immunosuppressive therapy.
A 55-year-old man comes to the outpatient clinic complaining of right toe pain for the past 8 hours. He is diagnosed with acute gouty arthritis. Which of the following is the recommended drug for this patient?
Answer: B
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
84
GastrCoheanptteerroTloitglye #4
Learning Objectives
List diseases that should be considered for presenting complaints of epigastric pain, diarrhea, or constipation
Describe the presentation and management of a patient with GI bleed
Describe the epidemiology and management of diseases of the esophagus, liver, pancreas, and colon including cirrhosis, acute pancreatitis, and colon cancer
Describe the types of malabsorption syndrome, their causes, and treatment
Differentiate diverticular disease and different forms of IBD in terms of their presen- tation and treatment
Most diseases of the esophagus will result in dysphagia (difficulty swallowing), yet only a few of them will result in pain on swallowing (odynophagia). Both dysphagia and odynophagia will cause weight loss if symptoms persist for more than a few days.
Dysphagia can be classified as oropharyngeal or esophageal. Oropharyngeal dysphagia is caused by muscular and neurologic disorders, such as stroke, Parkin-son, ALS, NG, muscular dystrophy, or Zenker’s diverticulum. Evaluation includes select videofluoroscopy (modified barium swallow); the patient swallows food under fluoroscopy and the upper esophageal sphincter is evaluated as the initial swallow is made. Patients with this condition present with:
Coughing with swallowing
Choking
Nasal regurgitation with fluids
Aspiration while swallowing
Patients with esophageal dysphagia report food “sticking” or discomfort in the retrosternal region.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
85
USMLE Step 2 l Internal Medicine
Achalasia
A 32-year-old woman with no past medical history comes to your office for the evaluation of “difficulty swallowing” foods. She reports food “sticking” in her chest. She has had this problem for almost a year, and it is most difficult for her to eat solids. Her symptoms have not worsened at all over this time period, and her weight has been stable. Physical examination is unremarkable. What is the next step in evaluation?
Achalasia is caused by degeneration of the myenteric plexus with loss of the normal inhibitory neural structure of the lower esophageal sphincter (LES). There is failure of the LES to relax and decreased peristalsis. The LES is usually contracted to prevent the acidic gastric contents from refluxing backward into the esophagus.
The vast majority of cases are of unknown etiology. A very small number can be from Chagas disease, gastric carcinoma, or a disease that can infiltrate into the area such as lymphoma.
Clinical Presentation. Achalasia presents with progressive dysphagia to both solids and liquids simultaneously and can have regurgitation several hours after eating. The patient complains of esophageal dysphagia with possible weight loss. Achalasia has no relationship with alcohol or tobacco use. This is different from esophageal cancer, which not only usually presents with dysphagia to solid foods and progresses to difficulty swallowing liquids, but also is more common in older patients with a long history of alcohol and tobacco use.
Diagnosis. Heme-positive stools, >6-month duration of symptoms, and weight loss will confirm diagnosis. Barium esophagography is very accurate and shows dilation of the esopha- gus, which narrows into a “bird’s beak” at the distal end. The most accurate test overall (gold standard) is esophageal manometry, which shows increased lower esophageal (LES) resting pressure and absence of peristalsis.
Diagnostic evaluation should done in the following order:
Upper endoscopy (to rule out adenocarcinoma [pseudoachalasia])
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
86
Chapter 4 ● Gastroenterology
Wikimedia, Farnoosh Farrokhi and Michael F. Vaezi
Treatment. The best initial therapy is pneumatic dilation or laparoscopic surgical myotomy.
Pneumatic dilation effective in 80–85% of patients, with 3–5% risk of perforation
Botulinum toxin injections into the LES is second-line treatment, to relieve symptoms for 6 months; also used for patients who are poor surgical candidates, e.g., the elderly with multiple comorbid conditions
Calcium channel blockers and nitrates are third-line treatment
Esophageal Cancer
A 62-year-old man comes for evaluation of progressive “difficulty swallowing solids and, recently, semisolids” for 4 months. He has noticed a 20-lb weight loss. His past medical history is significant for reflux esophagitis for 15 years and a 40-pack-year smoking history. On physical examination a 1.5-cm, left supraclavicular lymph node is found. The remainder of the physical examination is unremarkable.
Esophageal cancer is linked to the synergistic, carcinogenic effect of alcohol and tobacco use for cases of squamous cell cancer in the proximal two-thirds of the esophagus. Adenocarci- noma is found in the distal third of the esophagus and is associated with long-standing GERD and Barrett esophagus. The rate of development of cancer from Barrett esophagus is 0.4–0.8% per year. Squamous and adenocarcinoma are now of equal frequency.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
87
USMLE Step 2 l Internal Medicine
Clinical Presentation. Esophageal cancer presents with progressive dysphagia first for solid food, then for liquids. Weight loss is prominent. Rarely, halitosis, regurgitation, and hoarseness occur. Hypercalcemia may arise, as it can with most cancers.
To diagnose, do barium swallow first, but endoscopy is mandatory because this is a diagnosis that requires a tissue biopsy. CT scan detects the degree of local spread, and bronchoscopy detects asymptomatic spread into the bronchi. Endoscopic U/S is performed for staging.
Treatment. The only truly effective therapy for esophageal carcinoma is surgical resection if the disease is sufficiently localized to the esophagus. Only 25% of patients are found to be operable. Five-year survival is 5–20%. Chemotherapy with a 5-fluorouracil-based chemothera- py is combined with radiation to control locally metastatic disease.
Scleroderma (Progressive Systemic Sclerosis)
As many as 80–90% of patients with scleroderma will develop diminished esophageal peristal- sis from the atrophy and fibrosis of the esophageal smooth muscle.
Clinical Presentation. Although there is dysphagia, the main clue to the diagnosis is simply the presence of gastroesophageal reflux symptoms in a person with a history of scleroderma. The LES will neither contract nor relax and basically assumes the role of an immobile open tube.
The most accurate diagnostic test is a motility study. Barium studies are generally unnecessary.
Treatment. Treatment is a proton-pump inhibitor e.g., omeprazole. Metoclopramide, a promo- tility agent, has some modest effect.
Diffuse Esophageal Spasm and Nutcracker Esophagus
A 34-year-old man complains of “crushing” chest discomfort for 1 hour. He has no significant medical history. The ECG is normal. He is given sublingual nitroglycerin in the emergency room that improves his chest pain almost immediately.
Esophageal spastic disorders are idiopathic abnormalities of the neural processes of the esopha- gus. Fundamentally, diffuse esophageal spasm and nutcracker esophagus are the same disease; the only difference may be in the manometric pattern.
Clinical Presentation. Patients present with intermittent chest pain and dysphagia. The pain can simulate that of a myocardial infarction, but it bears no relationship with exertion. There is no relationship with eating, ruling out odynophagia. The pain can be precipitated by drinking cold liquids.
Barium study may show a “corkscrew”’ pattern at the time of the spasm. The most accurate test for diagnosis is a manometric study, which will show high-intensity, disorganized contractions. Because the contractions are disorganized, they do not lead to the forward flow of food and peristalsis.
Treatment is a calcium-channel blocker e.g., nifedipine, or a nitrate.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
88
Chapter 4 ● Gastroenterology
Rings and Webs
Schatzki’s ring and Plummer-Vinson syndrome reveal thin, epithelial membranes made out of squamous epithelial cells. Neither is progressive in nature, distinguishing them from achalasia.
Schatzki’s ring (more common) leads to intermittent dysphagia and is not associated with pain. It is more distal and located at the squamocolumnar junction proximal to the lower esophageal sphincter.
Plummer-Vinson syndrome (PVS) is more proximal and is located in the hypopharynx. The dysphagia can occur with liquids as well. PVS is associated with iron-deficiency anemia and squamous cell cancer; it most often occurs in middle-aged women.
Both disorders are diagnosed with a barium swallow or barium esophagoram.
Treatment. PVS may respond to treatment for the iron deficiency. Both are treated with dilation procedures.
Esophagitis
Esophagitis refers either to infection or inflammation of the esophagus. The most common infection is from Candida albicans. When Candida esophagitis occurs, it is almost exclusively in patients who are HIV-positive with CD4 count <200/mm3 (often even <100/mm3). The second most common risk for developing Candida esophagitis is diabetes mellitus. Much rarer infectious etiologies are herpes simplex, cytomegalovirus, and aphthous ulcers.
Barium swallow is the incorrect step for esophagitis. It is always the correct first step for dysphagia.
Clinical Presentation. Candida esophagitis presents with progressive odynophagia. Although the swallowing is painful, food is still able to pass (until the disease is extremely advanced).
Note that the pain in esophagitis is only on swallowing, while the pain in spastic disorders is intermittent without even needing to swallow.
Esophagitis pain is simply from the mechanical rubbing of food against an inflamed esophagus as it passes by.
Treatment. If the patient is HIV-positive, assume Candida esophagitis and start fluconazole; improved symptoms will confirm the diagnosis. If symptoms do not improve, perform endoscopy and biopsy to exclude other causes such as HSV and CMV.
Note that the treatment for Candida must be fluconazole. Nystatin swish and swallow will not work (and is a common incorrect answer on the exam).
35% of patients with Candida esophagitis will not have oral thrush (an absence of oral candida does not rule out esophageal candida)
Because esophagitis can also result from ingestion of medication and caustic substances, the direct effect of contact between the mucosa and the pill causes inflammation rather than infection. As with most other toxin-mediated damage to an organ, diagnosis is based on the presentation and identification of the toxin in the history. The most common pills causing esophagitis are alendronate, quinine, risedronate, vitamin C, potassium chloride, doxycycline, NSAIDs, and iron sulfate. Consider pill esophagitis in a young patient who takes acne medication and who has an acute onset of odynophagia.
Pill esophagitis is prevented by simply swallowing pills in the upright position and drinking enough water to flush them into the stomach.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
89
USMLE Step 2 l Internal Medicine
Eosinophilic Esophagitis
A young man with a history of allergies, asthma, or eczema presents with extreme solid food dysphagia. Upper endoscopy shows stacked circular rings and mucosal furrowing.
Biopsy shows marked infiltration with eosinophils. Also, there will be no improvement after an 8-week trial of PPIs.
GERD can also cause esophageal eosinophilia and can mimic EE. Therefore, GERD must be ruled out by a lack of response to an 8-week trial of PPIs. If the patient improves with PPIs, the diagnosis is GERD and not EE.
Treatment. Treat with swallowed fluticasone or budesonide. If the biopsy shows eosinophils, give PPIs before swallowed steroids.
Zenker diverticulum is the outpocketing of the posterior pharyngeal constrictor muscles at the back of the pharynx.
Wikipedia, James Heilman, MD
Figure 4-2. Zenker Diverticulum
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
90
Chapter 4 ● Gastroenterology
Clinical Presentation. Zenker diverticulum is a very slowly developing problem that occurs in older patients.
Bad breath
Difficulty initiating swallowing (due to such a proximal lesion)
Need to repeatedly clear the throat
Waking up with undigested, regurgitated food on the pillow (food from perhaps several days ago)
Barium study will confirm diagnosis.
Treatment. Treat with surgical resection. Endoscopy and the placement of nasogastric tubes are contraindicated because they could perforate the pharynx.
Mallory-Weiss syndrome is a nontransmural tear of the lower esophagus that is related to repeated episodes of retching and vomiting.
Clinical Presentation. Although Mallory-Weiss syndrome is an esophageal disorder, the pre- sentation is markedly different from the other problems described.
No dysphagia or odynophagia, but rather, painless upper GI bleed
Black stool from melena if volume of bleed >100 mL or with hematemesis if there is continued vomiting
Diagnosis is made with direct visualization on upper endoscopy.
Treatment. Typically, Mallory-Weiss tears will resolve spontaneously. It may be necessary to inject the tear with epinephrine or perform cauterization.
Clinical Recall
Barium swallow
Contrast CT of the chest
Endoscopy
Endoscopic ultrasound
Esophageal manometry
Answer: A
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
91
USMLE Step 2 l Internal Medicine
Note
All patients with epigastric pain should undergo endoscopy, except those age <50 with no alarm symptoms, such as bleeding, weight loss, or difficulty swallowing. Any alarm feature requires upper endoscopy.
EPIGASTRIC PAIN
In most cases, there is no definite way to determine the etiology of epigastric discomfort or pain simply by examining the patient’s history. Epigastric pain can be caused by the following:
Pancreatitis (most common reason for epigastric tenderness and pain)
Ulcer disease (associated with epigastric tenderness in <20% of patients)
GERD
Gastritis
Gastric cancer (rare)
Helicobacter pylori is most strongly associated with the development of duodenal ulcers, gastric ulcers, and gastritis.
Despite these diagnostic possibilities, the most common etiology of epigastric pain is, in fact, never truly determined. This is referred to as nonulcer dyspepsia, a functional disorder in which there is persistent pain in the epigastric area but all tests are found to be normal.
Guidelines recommend upper endoscopy for patients with dyspepsia and alarm features, so the first step is to look for those. Alarm features include the following:
Abdominal mass or lymphadenopathy on examination
Any alarm feature requires upper endoscopy. Endoscopy is also indicated if symptoms have not resolved with antisecretory therapy, such as PPIs.
For patients age <50 without alarm features, use a test-and-treat approach for H. pylori,
not endoscopy.
Treatment. Although endoscopy is the most accurate way to diagnose an ulcer, one can empirically treat ulcers, reflux disease, and gastritis.
Treat young, generally healthy patients empirically with H2 blocker, liquid antacid, or PPI; if no improvement, undergo endoscopy.
For patients without duodenal/gastric ulcer or gastritis, do not treat for H. pylori.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
92
Chapter 4 ● Gastroenterology
Gastroesophageal Reflux Disease
A 32-year-old man comes to the emergency department for substernal chest pain of 2 hours’ duration. He says that he sometimes gets this pain while lying in bed at night. He is otherwise free of symptoms, except for a nonproductive cough that he has had for the past month or so. Physical examination is unremarkable. ECG is normal. He is given sublingual nitroglycerin and notes that his chest discomfort is worsened.
Gastroesophageal reflux disease (GERD) is caused by the abnormal flow of the acid gastric contents backward from the stomach up into the esophagus. The lower esophageal sphincter (LES) is not a true anatomic sphincter (it cannot be found in a cadaver); it is created by the different response of the smooth muscle cells in the distal esophagus.
A number of factors can cause decreased tone or loosening of this sphincter.
Anticholinergics
Nitrates
When the tone of the LES decreases, acid is more likely to reflux backward into the esophagus, particularly when the patient is lying flat. GERD can still occur in the absence of these precipitating factors and can often simply be idiopathic in origin.
Clinical Presentation. GERD will present with heartburn (burning substernal pain); sore throat; a metal-like taste in the mouth; hoarseness; cough and wheezing. In addition, it is often associated with pain in the substernal area. Symptoms are worse after a meal or while lying flat.
The most accurate diagnostic test is a 24-hour pH monitor; an electrode is placed several centimeters above the gastroesophageal junction, and a determination is made of what the average pH is in that area. Normal endoscopy does not exclude reflux disease.
Note the following order when working up GERD:
Initiate PPI; if no improvement, increase PPI to 2x daily (before EGD) for 4–8 weeks and make sure patient is taking properly (30–60 min before meals)
If no improvement, do EGD: If EGD shows esophagitis, that confirms GERD and
24-hour pH monitoring is not needed. If EGD is normal, do ambulatory 24-hour pH monitoring (while off the PPI) and if results are consistent with GERD, do Nissen fundoplication.
In clear cases of epigastric pain going under the sternum and associated with a respiratory complaint or bad taste in the mouth, initiate therapy immediately with antisecretory medica- tions such as PPIs.
Note
There is no point in treating
pylori without evidence of disease such as gastritis or ulcer disease.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
93
USMLE Step 2 l Internal Medicine
Note
In patients with chronic cough (≥8 weeks), symptoms typical of GERD (heartburn, cough
that is worse after a large meal), and negative chest
ray, initiate a PPI as the next most appropriate step.
Treatment. Treatment is a PPI and lifestyle modification (avoid nicotine/alcohol/caffeine/ chocolate/late-night meals and elevate the head of the bed 6–8 inches with blocks to keep acid in the stomach)
Omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole are all equally effective PPIs; they will increase the pH of the gastric contents to a level >4.0.
PPI side effects include increased risk for C. difficile infection, aspiration pneumonia, osteoporosis, and hip fracture.
A few people (<5%) will not respond to PPIs or will have refractory side effects (headaches, diarrhea); those patients will require surgery to tighten the sphincter (traditionally, a Nissen fundoplication is done laparoscopically).
– Do motility studies prior to surgery to avoid iatrogenic dysphagia.
Use H2 blockers only if the patient has very mild, intermittent symptoms, as they are less effective than PPIs.
Barrett esophagus is a complication of long-standing reflux disease. After several years of GERD, the epithelium of the lower esophagus undergoes histologic change from a normal squamous epithelium to a columnar epithelium.
Men age ≥50 with chronic GERD (5+ years) and additional risk factors (nocturnal symptoms, hiatal hernia, obese, smokers) should be screened.
Patients with Barrett esophagus should have repeat endoscopy every 3–5 years to see wheth- er dysplasia or esophageal cancer has developed:
If high-grade dysplasia, do radiofrequency ablation, photodynamic therapy, or endoscopic mucosal resection
The usual rate of progression to cancer is about 0.5% per year. Do not check barium swallow, as it will be normal.
Treatment. All patients with Barrett esophagus should receive PPIs.
Peptic Ulcer Disease
Peptic ulcer disease includes both duodenal and gastric ulcers.
Tobacco smoking, alcohol, and steroids by themselves do not cause ulcer disease, although tobacco and alcohol can delay healing and are associated with the development of gastritis.
NSAIDs can cause ulcer formation because they decrease the normal production of the mucous barrier protecting the epithelial cells of the gastric mucosa. Prostaglan- dins, the major stimulant for mucous production that forms this protective barrier, are inhibited by NSAIDs and hence diminish the protective barrier of the stomach lining.
Steroid use by itself does not cause peptic ulcer disease and is therefore not a routine indication for stress ulcer prophylaxis.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
94
Chapter 4 ● Gastroenterology
Parietal cells in the stomach produce acid. The 3 stimulants to the production of acid from the parietal cells are gastrin, acetylcholine, and histamine.
Gastrin is produced by G cells in the stomach, and its release is stimulated by disten- tion of the stomach, the presence of amino acids, and vagal stimulation. Vagal stimulation also releases acetylcholine and gastrin-releasing peptide. However, the single most important stimulant to gastrin release is distention of the stomach.
Histamine is released by enterochromaffin-like cells present in the same glandular ele- ments of the stomach that have the parietal and chief cells. Chief cells release pepsino- gen, which is converted to pepsin by the acid environment of the gastric lumen. Histamine directly stimulates the parietal cells to both release acid and potentiate the effects of acetylcholine and gastrin on the parietal cells. This is why H2 blockers such as cimetidine, famotidine, and ranitidine inhibit acid release.
Zollinger-Ellison syndrome is the excessive production and release of gastrin from the pancreas. Somatostatin is the counterbalance to this system, inhibiting the release of gastrin and histamine, as well as having a direct inhibitory effect on the production of acid from the parietal cells. Secretin is released from the S cells of the duodenal lining. The main stimulant to the release of secretin is the presence of acid in the duodenum. Secretin inhibits the produc- tion of gastrin, as well as stimulates pancreatic and biliary bicarbonate production and release.
The most common cause of ulcer disease is Helicobacter pylori followed by the use of NSAIDs; 80–90% of duodenal ulcers and 70–80% of gastric ulcers are associated with
pylori. Overall, 10–20% of ulcers are idiopathic, and no clear etiology is ever identified.
Clinical Presentation. The most common presentation of ulcer disease is midepigastric pain. There is no definite way to distinguish between duodenal and gastric ulcer simply by symp- toms. Gastric ulcer is often associated with pain on eating (frequently leading to weight loss), while duodenal ulcer is thought to be relieved by eating. However, these associations are only rough approximations, and endoscopy is still required for a definite diagnosis.
Tenderness of the abdomen is unusual with ulcer disease. More than 80% are not associated with abdominal tenderness in the absence of a perforation. Nausea and vomiting are occasion- ally found with both of them.
Diagnosis. Ulcer disease is best diagnosed with upper endoscopy. Barium studies are inferior.
If patient age <50 and has no alarm symptoms, test and treat for H. pylori. If H. pylori is negative, give trail of proton-pump inhibitors (PPIs). If symptoms persist, perform endoscopy.
If patient age >50 or has alarm symptoms (weight loss, anemia, heme-positive stools, or dysphagia), perform endoscopy.
The diagnosis of H. pylori is based on urea breath testing, stool antigen testing, or biopsy with histology or rapid urease testing. The first 2 tests are non-invasive. Before testing for H. pylori, make sure the patient is off PPIs for 2 weeks and antibiotics for 4 weeks, as they can
cause false-negatives. Biopsy with histology can be done on treatment. Biopsy with rapid urease testing can also be false-negative on treatment.
Do not check serum antibodies as they will not indicate whether this is a past or present infection.
Treatment. The treatment of ulcer disease centers largely on the treatment of H. pylori. Use a proton pump inhibitor (PPI) combined with clarithromycin and amoxicillin. The PPIs omepra- zole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole are all equal in efficacy.
Note
For burn victims >30 % BSA and intubated patients, the correct answer is stress ulcer prophylaxis is.
Note
Gastric ulcers must be
biopsied to exclude cancer.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
95
USMLE Step 2 l Internal Medicine
The PPI/clarithromycin/amoxicillin regimen should be effective in >90% of patients. The other 2 choices of antibiotics are tetracycline and metronidazole.
Bismuth subsalicylate is not necessary.
Regimens that contain PPIs are superior to those that use H2 blockers, such as ranitidine or cimetidine.
The duration of therapy is 10−14 days, but sometimes the PPI is continued for a few months in order to heal the gastric mucosa.
Repeat endoscopy for gastric ulcers is needed only if symptoms persist or if biopsies were not done the first time. Follow-up endoscopy for duodenal ulcers is not required.
Testing for eradication is indicated only for persistent symptoms, ulcers, or malignancy.
Wait 4−8 weeks after treatment to check for eradication. Do not use serology to test for eradication.
If the organism was not eradicated, then repeat treatment with different antibiotics, plus bismuth subsalicylate. Explore sensitivity testing for the organism.
If the organism was eradicated and the ulcer persists or worsens, consider evaluating the patient for Zollinger-Ellison syndrome.
Ordinary ulcers not related to Helicobacter can be treated with PPIs alone. Stop NSAIDS. If unable to stop aspirin or NSAIDS, add a PPI, although COX-2 inhibitors are just as good as NSAIDS plus PPI. Sucralfate does not help and should not be used.
Give PPI for prophylaxis if patient is high risk. Risk factors include:
Concomitant use of aspirin (of any dose), anticoagulants, other NSAIDs, or glucocor- ticoids
Perforation
Refractory ulcers
Gastric outlet obstruction (can change endoscopic dilation)
Gastritis
Gastritis is inflammation, erosion, or damage of the gastric lining that has not developed into an ulcer.
Type B gastritis (most common) can be caused by alcohol, NSAIDs, Helicobacter, head trauma, burns, and mechanical ventilation. It is also associated with increased gastric acid production.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
96
Chapter 4 ● Gastroenterology
Type A gastritis is caused by atrophy of the gastric mucosa and associated with an autoimmune process such as vitamin B12 deficiency. It is also associated with dimin- ished gastric acid production and achlorhydria.
All patients with achlorhydria will have markedly elevated gastrin because acid inhibits gastrin release from G cells.
Mucosal-associated lymphoid tissue (MALT) leads to metaplasia as well as possible dysplasia and then to gastric cancer.
Clinical Presentation. Patients typically present with asymptomatic bleeding. When the gastritis is severe and erosive, abdominal pain will occur in the same area that patients with ulcer disease feel theirs. Nausea and vomiting may also occur. The bleeding can present as hematemesis or melena.
Diagnosis and Treatment.
Diagnosis and treatment of Helicobacter are the same as that for gastritis (described for ulcer disease above).
Diagnosis of vitamin B12 deficiency and pernicious anemia are made initially with low B12 and increased methylmalonic acid.
Zollinger-Ellison syndrome (ZES) is hypergastrinemia caused by cancer of the gastrin-producing cells. There is no known cause for gastrinoma or ZES. Half of these gastrinomas are located in the duodenum, and 25% in the pancreas. A small percentage (<20%) are associated with multiple endocrine neoplasia type 1 (MEN-1) or parathyroid, pituitary, and pancreatic tumor.
Clinical Presentation. More than 95% of patients with ZES present with ulcer disease. Fewer than 1% of people with ulcer disease have an underlying ZES or gastrinoma.
ZES presents with ulcers that are recurrent after therapy, multiple in number, occur in the distal portion of the duodenum, or are resistant to routine therapy. Diarrhea occurs in 70% of patients, i.e., ordinary watery diarrhea or steatorrhea (due to inactivated lipase from large volume of acid passed into the duodenum). Metastatic disease is evident at the time of diagnosis in 30% of patients; an additional 20% develop metastatic disease later.
Diagnosis. Although an elevated gastrin level is indicative of ZES, remember that all patients on H2 blockers or PPIs have elevated gastrin. That is because the main stimulus to the suppres- sion of gastrin release is acid. If acid production is suppressed, then gastrin goes up. So to diagnose ZES, gastrin must be found elevated after the patient has been off antisecretory therapy for several days.
Note
The presence of hypercalcemia is the clue to detecting MEN-1. This is because of the hyperparathyroidism.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
97
USMLE Step 2 l Internal Medicine
Diagnosis is the combination of elevated gastrin and increased gastric acidity (must check gastric pH to make diagnosis; if >4, it is not a gastrinoma). The secretin stimulation test is positive (abnormal) if there is a rise in gastrin level after the injection of secretin (normally, secretin should suppress gastrin release).
Other causes of increased gastrin include:
Pernicious anemia
Chronic gastritis
Renal failure
Hyperthyroidism
After confirming a diagnosis of gastrinoma, the most important step is to determine if the lesion is localized or metastatic.
Metastatic disease can be suppressed only with PPIs
– U/S, CT, and MRI have 60–80% sensitivity for the presence of metastatic disease— specific enough to prove the presence of tumor if positive but not sensitive enough to safely exclude disease if negative
A nuclear test, somatostatin-receptor scintigraphy, is 90% sensitive for the detection of metastatic disease. The single most sensitive test is the endoscopic U/S. Typically, both tests are done.
Treatment. Localized disease is surgically resected and metastatic disease is treated with the long-term administration of PPIs simply to block acid production.
Gastroparesis, or delayed gastric emptying, results in delayed movement of food from the stomach to the small intestine. The most common association is diabetes. Electrolyte problems with potassium, magnesium, and calcium can also weaken the musculature of the bowel wall.
Clinical Presentation. Patients with gastroparesis present with early satiety, postprandial nausea, and a general sense of increased abdominal fullness due to decreased motility of the stomach and the accumulation of food there. Gastroparesis generally occurs in those presenting with abdominal pain and bloating, and those with a long-standing history of diabetes, a
long-standing history of poor glycemic control, retinopathy, neuropathy, and nephropathy. It can accompany scleroderma, hypothyroidism, anti-cholinergic use, and narcotic use.
Diagnosis. Although gastroparesis is often diagnosed clinically, the gastric-emptying study is the confirmatory test; radioisotope-labeled food is ingested to measure transit time through the stomach. In a long-term diabetic, a diagnosis of diabetic gastroparesis is generally obvious as the cause of bloating, vomiting, and nausea, after endoscopy excludes other diseases. Make sure blood glucose <275 mg/dL before testing because severe hyperglycemia can impair gastric emptying.
Treatment. Treatment is agents that will increase motility of the stomach, such as erythromy- cin or metoclopramide. Also, smaller, more frequent portions of food are recommended, since emptying from the stomach is faster when there is less food.
Metoclopramide can cause tardive dyskinesia, Parkinsonism, and dystonia.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
98
Chapter 4 ● Gastroenterology
Dumping Syndrome
Dumping syndrome is an increasingly rare disorder because surgery is so infrequently needed anymore for ulcer disease. It was far more common in the past, when vagotomy and gastric resection were performed to treat severe ulcer disease.
Dumping syndrome is caused by 2 phenomena.
First, there is the rapid release of hypertonic chyme into the duodenum, which acts as an osmotic draw into the duodenum, causing intravascular volume depletion.
Next, there is a sudden peak in glucose levels in the blood because of the rapid release of food into the small intestine. This is followed by the rapid release of insulin in response to this high glucose level, which then causes hypoglycemia to develop.
Patients present with sweating, shaking, palpitations, and lightheadedness shortly after a meal.
Treatment. Treatment is supportive. Eat multiple, small meals.
Nonulcer Dyspepsia
When all the causes of epigastric pain have been excluded and there is still pain, fullness, or burning sensation, the diagnosis is nonulcer (or functional) dyspepsia. The cause of nonulcer dyspepsia is unknown.
If there are no alarm symptoms, test and treat H. pylori. If negative, treat with PPI.
If there are alarm symptoms or refractory symptoms, do endoscopy.
Try a low-dose tricyclic antidepressant if symptoms do not respond to PPI or H2-blocker therapy.
Clinical Recall
A 36-year-old man complains of intermittent, worsening epigastric pain radiating to the back for the past 3 months. The patient claims to drink alcohol only during business trips but admits to blacking out several times from too much alcohol. Which of the following is the most likely cause of his symptoms?
Barrett’s esophagus
Candida esophagitis
Gastritis
GERD
Pancreatitis
Answer: E
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
99
USMLE Step 2 l Internal Medicine
Note
Sclerosing cholangitis does not correlate to disease activity.
Note
Always check stool studies, especially C. difficile toxin during a flare.
Note
Check thiopurine methyltransferase level before starting azathioprine and
mercaptopurine; they are contraindicated in 1 in 300 patients who lack this enzyme and are at high risk for drug toxicity. Do not give allopurinol or febuxostat with these drugs (they are also metabolized by
INFLAMMATORY BOWEL DISEASE
Inflammatory bowel disease (IBD) describes 2 disease entities: Crohn’s disease (CD) and ulcerative colitis (UC). They can be discussed simultaneously because of the large degree of overlap in terms of presentation, testing, and treatment.
Idiopathic disorders of the bowel associated with diarrhea, bleeding, weight loss, fever, and abdominal pain
Most accurately diagnosed with endoscopy and sometimes barium study, “string sign” on small bowel follow through after barium meal in CD
Treat with anti-inflammatory medications such as mesalamine, azathioprine, and 6-mercaptopurine (6MP); steroids are reserved for acute exacerbations
Clinical Presentation. IBD presents with fever, diarrhea, weight loss, and, occasionally, abdominal pain and bleeding. The extraintestinal manifestations of IBD are episcleritis, scleritis and iritis, sclerosing cholangitis, joint pains, and skin manifestations, such as pyoder- ma gangrenosum or erythema nodosum.
Linear, stellate deep ulcerations with skip lesions involving entire GI tract | Mucosal edema, erythema, friability, ulceration |
Bloody diarrhea common; diarrhea promi- nent, tenesmus, urgency, hematochezia | |
Altered crypt architecture with shortened branched crypts and crypt abscesses | |
Rectum always involved | |
Limited to large bowel | |
No skip lesions, anal involvement, or fistulas | |
Complications include diarrhea, calcium oxalate kidney stones, and cholesterol gallstones |
Diagnosis. IBD is diagnosed with endoscopy and sometimes barium study. (CD can cause deficiency of B12, K, calcium, and iron because of malabsorption.)
Anti–Saccharomyces cerevisiae antibodies (ASCA) are associated with CD, while antineutrophil cytoplasmic antibody (ANCA) is associated with UC.
If a patient is ASCA-positive and ANCA-negative, he has a >90% chance of having CD.
If a patient is ASCA-negative and ANCA-positive, he has a >90% chance of having UC.
With CD, prothrombin time may be prolonged because of vitamin K malabsorption. Also, kidney stones are more often seen because the fat malabsorption causes reduced calcium and increased absorption of oxalate. Use cholestyramine to treat calcium oxalate stones.
Treatment. Therapy is divided into active and maintenance.
xanthine oxidase).
100
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
Chapter 4 ● Gastroenterology
Table 4-2. Treatment of CD versus UC
Crohn’s Disease | Ulcerative Colitis |
5-ASAs are often ineffective | Depends on severity of disease |
Mild: For active disease prednisone or budesonide For maintenance azathioprine and 6-mercaptopurine | Mild: 4 bowel movements/day, mild bleeding, normal labs Mesalamine or sulfasalazine (causes reversible infertility in men and leukopenia by its sulfapyridine group) |
Moderate: fever, weight loss, anemia, abdominal pain, nausea/vomiting For active steroids For maintenance azathioprine and 6-mercaptopurine or methotrexate | Moderate: 4–6 bowel movements/day For active disease prednisone For remission budesonide |
Severe to fulminant: high fever, vomiting, rebound, obstruction For acute exacerbations, IV steroids or anti-TNF (better choice), possible surgery | Severe: >6 bowel movements/day, bleeding, fever, tachycardia, ESR >30 mm/h, anemia |
Fistula: anti-TNF For induction and maintenance anti-TNF antibodies (infliximab, adalimumab, certolizumab); if anti-TNF fails (can cause PML so check JC virus antibodies first) natali- zumab (a monoclonal antibody to integrin-alfa-4 on leukocytes) | |
For those with perianal disease ciprofloxacin and metroni- dazole For those who form fistulae or have disease refractory to other therapies infliximab | |
Surgery is not very effective; disease tends to reoccur at the site of anastomosis | Surgery is curative; almost 60% of patients will require surgery within 5 years after diagnosis due to refractory symptoms or severe disease |
For both, start screening colonoscopy 8–10 years after diagnosis and repeat every 1–2 years.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
101
USMLE Step 2 l Internal Medicine
Note
Check PPD, HBV, HCV prior to initiating anti-TNF agent.
Note
With management of diarrhea, determine when to admit the patient and when to use IV fluids and antibiotics. That is more important than determining the precise causative agent.
DIARRHEA
Diarrhea is increased frequency or volume of stool per day (alternatively, it can be defined as few stools per day but with watery consistency). The most common causes include an infec- tious, antibiotic-associated, or lactose-intolerance etiology, irritable bowel syndrome, and carcinoid syndrome.
The patient is often hypotensive, febrile, and experiencing abdominal pain.
Diagnosis. The first step in the evaluation of diarrhea is to see if there is hypovolemia as defined as hypotension or orthostasis. This is more important than determining specific etiology because the patient could die while waiting for the results to come back.
Treatment. No matter the etiology, if the patient is hypotensive, febrile, and having abdominal pain, admit as inpatient and give IV fluids and antibiotics. Blood in the stool is especially serious, and is probably the single strongest indication for the use of antibiotics, such as ciprofloxacin.
The majority of acute diarrhea is viral and self-limited. Clostridium difficile toxin and stool
Giardia-antigen testing are done when there are clues to these diagnoses in the history.
With bacterial diarrhea, the most common causes are Campylobacter and Salmonella, espe- cially in patients with sickle cell and achlorhydria. A definitive determination of the etiology can only be made with a stool culture.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
102
Chapter 4 ● Gastroenterology
Table 4-3. Clues to the Diagnosis of Infectious Diarrhea Prior to Results of Culture
Causative Agent | Patient Symptoms or History | Additional Comments |
Bacillus cereus |
| Short incubation period (1–6 hours) |
Campylobacter | Reactive arthritis, Guillain-Barré syndrome | Most common cause of bacterial gastroenteritis |
Cryptosporidia, Isospora | Found in HIV-positive patients with <100/mm3 CD4 cells | — |
E. coli 0157:H7 | ||
Giardia | If not eradicated, can simulate celiac disease in terms of causing fat and vitamin malabsorption | |
Salmonella | ||
Scombroid | Ingestion of contaminated fish; almost immediate vomiting, diarrhea, flushing, and wheezing | |
Shigella, Yersinia | No clues strong enough to point to etiology until the results of stool culture are known | Yersinia can mimic appendicitis. Also common in people with iron overload, e.g., hemochromatosis. |
Vibrio parahaemolyticus | Ingestion of raw shellfish, such as mussels clams | Typically presents as severe systemic gastroenteri- tis in patients with underlying disease (esp. chronic liver disease) |
Vibrio vulnificus | Ingestion of raw shellfish (particularly affects those with underlying liver disease) Skin bullae | Typically presents as severe systemic gastroenteri- tis in patients with underlying disease (esp. chronic liver disease or disorders of iron metabolism) |
Viral | Children in day-care centers; absence of blood and white cells | No systemic manifestation |
Staphylococcus aureus |
| Short incubation period (1–6 hours) |
Ciguatera-toxin | Ingestion of large reef fish (grouper, red snapper, barracuda); 2–6 hours after inges- tion, neurological symptoms leading to paresthesia, weakness, reversal of hot/cold | — |
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
103
USMLE Step 2 l Internal Medicine
Note
TMP/SMX for Isospora
Doxycycline for Vibrio vulnificus
Rifaximin for travelers’ diarrhea
Note
Prophylactic antibiotics for traveler’s diarrhea is never a correct approach.
Diagnosis. Only send stool studies if condition does not resolve in 1 week. Invasive organisms need 24–36 hours to produce their effect and never produce blood in the stool within the first few hours of ingestion (except the protozoan Entamoeba histolytica, which can give blood or white cells in stool). The most definitive test for these bacterial organisms is stool culture.
The invasive organisms are:
Salmonella
Shigella
Campylobacter
Vibrio parahaemolyticus
Yersinia
E. coli
Vibrio vulnificus (think people drinking sea water)
Cryptosporidiosis diagnosis requires a unique test—a modified acid-fast test; it cannot be detected reliably by the routine ova and parasite exam.
Giardia diagnosis is best made with an ELISA stool antigen test (a single test has 90% sensitivity, whereas 3 stool ova and parasite exams have only 80% sensitivity). Consider this for chronic diarrhea in patients exposed to young children or who drank water from a lake or stream.
Treatment. Most cases of food poisoning and infectious diarrhea will resolve spontaneously and will not need antimicrobial therapy. Even when they cause severe disease, as defined by high-volume stools with dehydration, antibiotics generally do not help. Use antibiotics if there is abdominal pain, blood in the stool, and fever >7 days.
The decision to use antibiotics is always made prior to knowing the result of the stool culture, so the treatment is always empiric and then modified when the culture results are known. The best empiric therapy for infectious diarrhea is ciprofloxacin or the other fluoroquinolones ± metronidazole.
Do not give antibiotics for E. coli 0157:H7, as that precipitate HUS.
Scombroid poisoning is treated with antihistamines, such as diphenhydramine. Giardia is still treated primarily with metronidazole. A newer agent for Giardia is tinidazole, which is effective in a single dose. Cryptosporidiosis is treated with nitazoxanide, although it has limited efficacy. The truly effective therapy for cryptosporidiosis is to raise the CD4 count to >100/mm3 with antiretrovirals. Nitazoxanide is superior to paromomycin for cryptosporidium.
There is no specific therapy for viral diarrhea. Patients are managed with fluid and electrolyte support until the infection resolves.
For chronic diarrhea (>4 weeks), think of the following:
Use of artificial sweeteners (get diet history)
Giardia if camping or exposed to children (daycare worker)
If bloating and discomfort are relieved by bowel movement with no weight loss: IBS, test for celiac
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
104
Chapter 4 ● Gastroenterology
If woman age 45–60, unrelated to food (nocturnal diarrhea), no abdominal pain or weight loss, normal colonoscopy, think microscopic colitis; biopsy must be done to diagnose (associated with NSAIDs and PPIs); treat with loperamide, bismuth, or budesonide (stop NSAIDs, PPIs)
Nocturnal diarrhea and diabetes or scleroderma or gastric bypass surgery: small bowel bacterial overgrowth: check hydrogen breath test or give empiric antibiotics
Flushing and wheezing: carcinoid syndrome; check urine 5-HIAA
Antibiotic- and C. difficile-Associated Diarrhea
Antibiotic-associated diarrhea (AAD) is a benign, self-limited diarrhea following the use of antimi- crobials. Typically, no pathogens are identified; the diarrhea is caused by changes in the composi- tion and function of the intestinal flora, as well as increased motility (common with agents like erythromycin). Most patients respond to supportive measures and discontinuation of antibiotics.
Clostridium difficile-associated diarrhea (C. diff) refers to a spectrum of diarrheal illnesses caused by the toxins produced by C. diff, including severe colitis with or without the presence of pseudomembranes. (For exam purposes, this discussion will focus on C. diff.)
Pathogenesis. Any antibiotic can lead to diarrhea with C. diff, although antibiotics that are broad spectrum are more likely to do so. Clindamycin may have one of the highest frequencies of association, as do fluoroquinolones and cephalosporins.
diff diarrhea is largely a nosocomial disease and is the most frequent cause of diarrhea in hospitalized patients. It occurs infrequently in the outpatient setting, other than in patients confined to nursing homes. Research suggests a significant association between C. difficile and the use of PPIs.
Clinical Presentation and Diagnosis. The clinical manifestations of C. diff may vary from mild diarrhea to fulminant colitis. If a patient develops diarrhea several days to weeks (even up to 8 weeks) after using antibiotics, evaluate for C. diff. Marked leukocytosis and systemic symptoms are evident in severe cases.
Until a few years ago, the diagnostic method of choice for C. difficile colitis was the enzyme-linked immunosorbent assay (ELISA), based on toxin detection in the stool. While ELISA is fast, inexpensive, and has excellent specificity, its sensitivity is variable (75−85%).
The newer preferred method of diagnosis is the nucleic acid amplification (LAMP, loop-mediated isothermal amplification) assay, which may include the real-time polymerase chain reaction (PCR) or loop-mediated isothermal amplification test (both of which detect the toxin A and B genes responsible for the production of toxins). LAMP has specificity 94−100% and sensitivity 90−100%. There is no benefit to testing multiple stool specimens or repeat testing following a positive test.
Treatment. Metronidazole is the drug of choice along with discontinuation of antibiotics (if feasible) and supportive therapy. If the diagnosis is highly likely and the patient is seriously ill, metronidazole may be given empirically before the test results. Oral vancomycin is reserved for the following conditions:
Failed therapy with metronidazole
Organisms resistant to metronidazole
Allergy or intolerance to metronidazole
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
105
USMLE Step 2 l Internal Medicine
Note
Do not use fidaxomicin for the first episode of C. diff colitis.
Pregnancy or young age (<10 years)
Severe C. diff (WBC >15,000 or increased serum creatinine >1.5 × normal)
If symptoms resolve but there is a recurrence (~30% in some studies), then retreat with metronidazole. Use IV metronidazole if patient is unable to use oral medication (This is not true of vancomycin, i.e., IV vancomycin will have no effect in the bowel because it does not pass bowel wall. Similarly, oral vancomycin will have no systemic effect.)
If there is a second recurrence, use a prolonged course of oral vancomycin taper (6–8 weeks). It must be 6 weeks to be effective and it must be tapered. Alternatively, consider fecal trans- plant or a new drug, fidaxomicin (note that this is not more effective than vancomycin or metronidazole for the first episode). Fidaxomicin seems to reduce the number of episodes of recurrent C. difficile colitis.
Lactose intolerance is perhaps the single most common potential cause of diarrhea because of the enormously high prevalence of lactase deficiency. This is a disorder so common that the testing and treatment are generally empiric.
The diarrhea produced is associated with gas and bloating, but never contains blood or leukocytes. Despite the malabsorption of lactose, weight loss does not occur.
Diagnosis can be confirmed with increased stool osmolality and increased osmolar gap.
Osmolar gap means that the difference between the osmolality measure in the stool and the osmolality calculated from the sodium and potassium levels is >50 mOsm/kg.
Other causes of an increased stool osmolar gap are magnesium and polyethylene glycol in the stool, or nutrient malabsorption leading to pancreatic insufficiency, celiac sprue, and bacterial overgrowth.
The routine way to diagnose lactose intolerance is simply to remove milk, cheese, ice cream, and other dairy products (except yogurt) from the diet and observe for resolution of symptoms, which should occur within 24–36 hours. (This differs from celiac disease, where resolution of diarrheal symptoms make take weeks after stopping the ingestion of gluten- containing foods.) If resolution of symptoms does occur, then dietary changes are the best therapy. The patient can use lactase supplements.
Irritable Bowel Syndrome
Although it is often described at the same time as diarrheal illnesses, irritable bowel syndrome (IBS) is predominantly a pain syndrome of unknown etiology. IBS is an idiopathic disorder in which there is increased frequency of the normal peristaltic and segmentation contractions of the bowel. Pain is often relieved by a bowel movement.
20% of patients have constipation only, while a large percentage have diarrhea alone or diarrhea alternating with constipation.
Everyone has pain.
There are no nocturnal symptoms.
There are no constitutional signs or symptoms, e.g., fever, weight loss, anorexia, or anemia.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
106
Chapter 4 ● Gastroenterology
Diagnosis. There is no specific diagnostic test for IBS. The first step is to exclude lactose intolerance, IBD, celiac disease, carcinoid, Giardia infection, and anatomic defects of the bowel as the cause.
The diagnostic criteria, called Rome criteria, must occur for at least 3 months:
Pain relieved by a bowel movement or by a change in bowel habit (e.g., when you develop diarrhea, the pain goes away)
Fewer symptoms at night
Diarrhea alternating with constipation
Colonoscopy is not needed for diagnosis, but a work up for celiac sprue must be done if diarrhea is predominant.
Treatment.
Antidiarrheal agent such as loperamide or diphenoxylate for diarrhea-predominant disease
Hyoscyamine or dicyclomine for abdominal pain (alternatively, tricyclic antidepressant or SSRI)
Osmotic laxative polyethylene glycol for IBD-C; lubiprostone (women) and linaclotide for IBD-C unresponsive to PEG
Do not use alosetron due to risk of ischemic colitis.
Carcinoid Syndrome
Carcinoid syndrome describes tumors of the neuroendocrine system. They are most often located in the appendix and ileum. By definition carcinoid syndrome implies metastatic disease (except for bronchial carcinoids). Until there is an enormous tumor burden, the liver is able to neutralize all of the serotonin released by the carcinoid in the bowel. This usually does not happen until the metabolic capacity of the liver has been overwhelmed by metastatic disease.
Bronchial carcinoids are rare but highly symptomatic because the serotonin produced is released directly into the circulation without being detoxified in the liver.
Clinical Presentation. Carcinoid syndrome presents with diarrhea, flushing, tachycardia, and hypotension. A rash may develop from niacin deficiency, a direct result of the carcinoid.
Serotonin and niacin are both produced from tryptophan, so if there is an overproduction of serotonin, a tryptophan deficiency and thus a niacin deficiency, will result. Endocardial fibrosis also occurs because of a constant exposure of the right side of the heart to the serotonin. This leads to tricuspid insufficiency and pulmonic stenosis.
Diagnosis. The diagnosis is confirmed with urinary 5-hydroxyindolacetic acid level (5-HIAA).
Treatment. Therapy is generally based on controlling the diarrhea with octreotide, a soma- tostatin analog. Very few carcinoids are sufficiently localized to be amenable to surgical resection. If a tumor does happen to be localized, then it should be resected. This is most often possible with bronchial carcinoid. Surgery is also used to relieve obstruction of the bowel.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
107
USMLE Step 2 l Internal Medicine
Clinical Pearl Antibodies Seen in Celiac Disease
IgA endomysial antibody
IgA tissue transglutaminase antibody
IgG tissue transglutaminase
antibody
IgA deamidated gliadin peptide
IgG deamidated gliadin
peptide
Anti-tissue transglutaminase antibody (IgA) is the most sensitive and specific. In patients with IgA deficiency, IgA endomysial and transglutaminase antibodies are falsely normal.
MALABSORPTION SYNDROMES
The major causes of fat malabsorption are celiac disease and chronic pancreatitis, although in extremely rare cases it is caused by tropical sprue or Whipple disease. What they all have in common is the production of diarrhea characterized as greasy, oily, floating, and fatty, with a particularly foul smell, as if fat were fermenting. This type of diarrhea with fat is called steatorrhea.
All malabsorption syndromes are characterized by weight loss because fat has the highest caloric content of all the foods. In addition, there is malabsorption of the fat-soluble vitamins A, D, E, and K.
Vitamin A deficiency: night blindness (early), complete blindness
Vitamin D deficiency: hypocalcemia hypophosphatemia, osteomalacia
Vitamin E deficiency: neuromuscular disorders, hemolysis
Vitamin K deficiency: prolongation of prothrombin time and easy bruising
Iron malabsorption occurs if there is involvement of the duodenum where iron is normally absorbed. Iron deficiency anemia is evident in all patients with celiac sprue. Macrocytic anemia occurs if folate is malabsorbed. Vitamin B12 malabsorption occurs from damage or loss of the mucosal surface of the terminal ileum.
Clinical Presentation. All malabsorption syndromes present with chronic diarrhea. The only unique feature of celiac disease is dermatitis herpetiformis, a vesicular skin rash on the extensor surfaces of the body (10% of patients). Even without dermatitis herpetiformis, celiac disease is the most likely etiology of fat malabsorption because it is the most common.
History of pain, recurrent attacks of acute pancreatitis, weight loss
If CT does not show calcifications, get MRCP to detect abnormal pancreatic ducts.
For young adults with chronic pancreatitis, work up for cystic fibrosis (especially if there is recurrent pneumonia, sinusitis, and infertility).
Suspect tropical sprue when there is a history of being in a tropical country, and Whipple disease (very rare) if there is dementia (10%), arthralgia (80%), and ophthalmoplegia.
Treatment. Treatment includes pancreatic enzymes; pain control with NSAID/acetamino- phen, tramadol (may cause hypoglycemia), tricyclic antidepressant, gabapentin, or pregabalin; insulin (required for diabetics, as it mimics type 1 diabetes due to destruction of beta cells). Do not use narcotics for pain control.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
108
Chapter 4 ● Gastroenterology
Celiac Sprue
Celiac sprue is secondary to ingestion of wheat, gluten, or related rye and barley proteins. Patients present with the following:
Chronic diarrhea or steatorrhea
Bloating, weight loss, abdominal pain
Pruritic papulovesicular rash on extensor surfaces (dermatitis herpetiformis)
Isolated abnormalities in liver chemistry tests
Unexpanded iron deficiency anemia (after a negative work up for GI bleed)
Fat-soluble vitamin deficiencies
Early onset osteoporosis
Strong association with type 1 diabetes (should be screened)
Malabsorption of thyroid hormone in patient with thyroiditis
IBS-D
The antibodies seen in celiac disease include IgA endomysial antibody, IgA tissue transgluta- minase antibody, IgG tissue transglutaminase antibody. Anti-tissue transglutaminase antibody (IgA) is the most sensitive and specific. In patients with IgA deficiency, IgA endomysial and transglutaminase antibodies are falsely normal. Check IgG anti-tTG.
Work up celiac in a patient with thyroiditis who is not responding to high doses of levothyroxine.
Diagnosis. The first step with celiac disease is to test for the presence of antiendomysial and anti-transglutaminase antibodies. The most accurate test is a small bowel biopsy, which shows flattening of villi. Even if the antibody tests confirm the diagnosis of celiac disease, the bowel biopsy should be done anyway to exclude small bowel lymphoma.
Just removing gluten (wheat, rye, oats) from the diet is not an accurate way to establish the diagnosis because the circulating antibodies will continue to be present for weeks after stopping the ingestion of gluten.
Tropical sprue and Whipple’s disease are diagnosed by finding organisms on a bowel-wall biopsy. The single most sensitive test for Whipple’s disease is a polymerase chain reaction (PCR) of the bowel biopsy. A positive Tropheryma whippelii biopsy shows foamy macrophages that are PAS positive.
Treatment. Celiac disease is managed by adhering to a gluten-free diet (no wheat, oats, rye, or barley); nonadherence is the most common reason for failure. Use dapsone when celiac patients have dermatitis herpetiformis.
Trimethoprim/sulfamethoxazole or doxycycline × 6 months (for tropical sprue)
Trimethoprim/sulfamethoxazole, doxycycline, or ceftriaxone × 1 year (for Whipple disease)
Although all malabsorption syndromes are associated with multiple deficiencies, note some complications:
Celiac disease is associated with GI lymphoma and adenocarcinoma; patients are at risk for adenocarcinoma of the intestine
Celiac sprue is associated with lymphoma (enteropathy-associated T cell lymphoma) (10-15% of cases); unclear whether therapy with gluten-free diet reduces incidence of lymphoma
Note
In chronic pancreatitis, lipase and amylase are usually normal due to a burnt out pancreas.
Clinical Correlate
Do not let the lack of diarrhea and weight loss keep you from considering celiac. Test for celiac in anyone with unexplained elevation in LFTs or multiple vitamin deficiencies.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc.
and the National Board of Medical Examiners.
109
USMLE Step 2 l Internal Medicine
Clinical Recall
A 22-year-old woman complains of intermittent bloating and diarrhea for the past 3 months. Her symptoms are relieved when she avoids her morning coffee and ice cream. On diagnostic testing, her blood and stool tests were within normal limits except for a mild elevation in stool osmolality. What is the most likely cause of her symptoms?
Celiac sprue
Carcinoid syndrome
Irritable bowel syndrome
Lactose intolerance
Answer: D
In diverticular disease, small bulges or pockets develop in the lining of the intestine. They often develop where the muscles are weakest, e.g., where penetrating vessels cross through muscle.
Diverticulosis is so common in older populations throughout the Western world (50% of persons age >50, with higher rates in older populations) that it is almost considered a normal part of aging. The cause of diverticulosis is believed to a lack of fiber in the diet to give bulk to stool. There is a subsequent rise in intracolonic pressure, leading to outpocketing of the colon.
Clinical Presentation. Most of the time, patients are asymptomatic. When symptoms do exist, they are typically left lower quadrant abdominal pain that is colicky in nature.
Diverticulosis is diagnosed with colonoscopy. Endoscopy is superior to barium study, particu- larly when bleeding is present. Diverticula are more common on the left in the sigmoid, but bleeding occurs more often from diverticula on the right because of thinner mucosa and more fragile blood vessels. When bleeding occurs from diverticula, it is painless.
Treatment. Treatment is an increased-fiber diet, as is found in bran, bulking agents such as psyllium husks, and soluble fiber supplements.
Diverticulitis
Diverticulitis occurs when one of the bulges or pockets (diverticula) becomes infected. This can occur when the diverticular entrance in the colon becomes blocked, perhaps by nuts or corn.
Diverticulitis is distinguished from uninfected diverticula by the presence of fever, tender- ness, more intense pain, and elevated white blood cell count.
Diagnosis is confirmed with CT scan. Barium study and endoscopy are contraindicated because there is a slightly higher risk of perforation.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
110
Chapter 4 ● Gastroenterology
Treatment. Diverticulitis is treated with antibiotics such as ciprofloxacin and metronidazole. The other choices are ampicillin/sulbactam, piperacillin/tazobactam, or combined cefotetan or cefoxitin with gentamicin. Mild disease can be treated with oral antibiotics such as amoxicil- lin/clavulanic acid. Do colonoscopy several weeks after recovery to evaluate.
CONSTIPATION
The most common cause of constipation is lack of dietary fiber and insufficient fluid intake. Calcium-channel blockers, oral ferrous sulfate, hypothyroidism, opiate analgesics, and medi- cations with anticholinergic effects such as the tricyclic antidepressants all cause constipation. In the patient above, the most likely cause of the constipation is the ferrous sulfate.
Very dark stool, as in this patient, occurs only with bleeding, bismuth subsalicylate ingestion, and iron replacement.
However, GI bleed produces diarrhea—not constipation—because blood acts as a cathartic.
Blood causes diarrhea, and iron tablets cause constipation.
Treatment. Stop all medications that cause constipation; then make sure the patient stays well-hydrated and consumes 20–30 grams of daily fiber.
Bulking agents, such as those used to manage diverticular diseases
Drug treatment: milk of magnesia, cascara, bisacodyl, docusate
Lactulose and polyethylene glycol
COLON CANCER
The lifetime risk of colon cancer is >6%. Most cases occur sporadically, which is to say there is no clearly identified etiology.
A diet high in red meat and fat leads to an increased risk, as does smoking.
When the cancer is in the right side of the colon, patients present with heme-positive, brown stool and chronic anemia.
When the cancer is in the left side or in the sigmoid colon, patients present with obstruction and narrowing of stool caliber.
That is because the right side of the colon is wider than the left, and the stool is more liquid in that part of the bowel, making obstruction less likely on the right.
Endocarditis by Streptococcus bovis and Clostridium septicum have a strong associa- tion with colon cancer. Anyone presenting with endocarditis due to one of these organisms requires a GI work-up.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
111
USMLE Step 2 l Internal Medicine
Diagnosis. Colonoscopy is the most accurate diagnostic test. Sigmoidoscopy will reach the lesion only within the distal 60 cm of the colon. If the lesion is in the distal area then the sigmoidoscopy will be equally sensitive as colonoscopy, but only 60% of cancers occur there. Barium study is not as accurate as colonoscopy, nor can you biopsy.
Treatment. Treatment depends on the stage of disease and extent of its spread.
Single liver metastatic lesion: surgical resection
Cancer localized to the mucosa, submucosa, and muscularis layers: surgical resection; curable
Cancer penetrated to the serosa and spread into surrounding tissue and lymph nodes: surgical resection not effective in eradicating disease
Widespread disease: chemotherapy (mainstay of chemotherapy for GI malignancies such as colon cancer is 5-fluorouracil [5FU])
Screening. The standard screening recommendation for colon cancer is as follows. Screening should occur in the general population after age 50.
High-sensitivity fecal occult blood testing (FOBT) every year
Combined high-sensitivity FOBT (every 3 years) plus flexible sigmoidoscopy (every 5 years) OR colonoscopy every 10 years
If adenomatous polyps were found on previous colonoscopy, repeat colonoscopy in 3–5 years. In cases of family history of colon cancer, begin screening at age 40 or 10 years earlier than the family member got cancer, whichever is younger (also see Preventive Medicine chapter).
Hereditary Nonpolyposis Syndrome (Lynch Syndrome)
Certain families carry a genetic defect with a high degree of penetrance for colon cancer. The genetic defect does not cause polyps, however. By definition, the syndrome is defined as:
Three family members in at least 2 generations with colon cancer
One of these cases should be premature, i.e., occurred in someone age <50
Patients with this syndrome are also at increased risk for ovarian and endometrial cancer (up to 30%).
Screening. Start screening at age 25 and undergo colonoscopy every 1–2 years.
Hereditary Polyposis Syndromes
Familial adenomatous polyposis has a very clear genetic defect. The adenomatous polyposis coli gene (APC) confers 100% penetrance for the development of adenoma by age 35 and of colon cancer by age 50. Polyps can be found as early as age 25. Start screening at age 12 and do flexible sigmoidoscopy every 1–2 years. As soon as polyps are found, perform a colectomy; a new rectum should be made from the terminal ileum.
By contrast, juvenile polyposis syndrome confers about a 10% risk of colon cancer. There are only a few dozen polyps, as opposed to the thousands of polyps found in those with familial polyposis. In addition, the polyps of the juvenile polyposis syndrome are hamartomas, not adenomas. Hamartomas confer very little risk of developing into cancer. There is no specific recommendation for screening.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
112
Chapter 4 ● Gastroenterology
Cowden syndrome is another polyposis syndrome with hamartomas that gives only a slightly increased risk of cancer compared with the general population. These polyposis syndromes can present with rectal bleeding in a child.
Other Polyposis and Colon Cancer Syndromes
Gardner syndrome is the association of colon cancer with multiple, soft-tissue tumors, such as osteomas, lipomas, cysts, and fibrosarcomas. Osteomas are frequently found on the mandible. If osteomas are found as an incidental finding on x-ray, do a colonoscopy.
Peutz-Jeghers syndrome is the association of hamartomatous polyps in the large and small intestine with hyperpigmented spots. These are melanotic spots on the lips, buccal mucosa, and skin. The risk of cancer is slightly increased above the general population. Most common presentation is with abdominal pain due to intussusception/bowel obstruction.
Turcot syndrome is simply the association of colon cancer with central nervous system malignancies.
Screening. There is no recommendation for increased cancer screening for any of these syndromes; they are not common enough to warrant a clear recommendation for uniform early screening. There is an association of endocarditis from Streptococcus bovis with colon cancer, so if a patient has endocarditis from S. bovis, colonoscopy should be performed.
The first thing to consider for a patient with GI bleed is the treatment, not the etiology.
Upper GI bleed is most commonly caused by ulcer disease, gastritis, Mallory-Weiss syndrome, esophagitis, and gastric cancer. By definition, upper GI bleed is defined as bleeding occurring proximal to the ligament of Treitz, which anatomically separates the duodenum from the jejunum. If there is a history of abdominal aortic aneurysm repair in the past 6 months to 1 year, consider aortoenteric fistula.
Variceal bleed is common in those with portal hypertension from cirrhosis.
Lower GI bleed is most commonly caused by diverticulosis, angiodysplasia (also know as AVM or vascular ectasia), hemorrhoids, cancer, and IBD.
Clinical Presentation. Typically, upper GI bleed presents with black stool or melena, while
lower GI bleed presents with red blood in the stool.
Upper GI bleed can also cause hematemesis if the volume of bleeding is high enough.
About 10% of cases of red blood from the rectum can be from an upper GI source. This can happen if the volume of blood is so high that it is rapidly transported to the bowel without time for it to oxidize and turn black.
In upper GI bleed, occult blood–positive brown stool can occur with as little as 5–10 mL of blood loss. Melena develops when at least 100 mL of blood has been lost.
Note
If osteomas are seen as an incidental finding on x-ray, perform a colonoscopy.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
113
USMLE Step 2 l Internal Medicine
Note
In >80% of cases, GI bleeding will resolve spontaneously with supportive management, irrespective of etiology.
Orthostasis is defined as a >10-point rise in pulse when the patient goes from the supine to the standing or sitting position. It is also defined as a >20-point drop in systolic blood pressure on a change in position. There should be at least a minute in between the position change and the measurement of the pulse and blood pressure to allow time for the normal autonomic dis- charge to accommodate to the position change.
Orthostasis is when the rise in pulse or drop in blood pressure persists after the position has been changed. It indicates a 15–20% blood loss. The measurement of orthostatic changes is not necessary in the patient described in this case because a pulse >100/min or a systolic blood pressure <100/min already indicates a >30% blood loss.
Diagnosis. Endoscopy is the most accurate test to determine the etiology of both upper and lower GI bleed. Barium study is always less accurate. Should biopsy be needed, an endoscopy must be performed.
Treatment. The most important step in the initial management of severe GI bleeding is to begin fluid resuscitation with normal saline or Ringer’s lactate. A complete blood count, pro- thrombin time, and type and crossmatch should be done, but if the patient is having a high vol- ume bleed as in the patient above, never wait for the test results to begin fluid resuscitation.
If prothrombin time is elevated above the control, prothrombin concentrate complex should be given, and IV vitamin K if on warfarin (replacing fresh frozen plasma)
Platelets should be transfused if platelet count <50,000/mm3 and if patient is actively bleeding
Nasogastric tube should not be used If upper GI bleed is suspected:
All of the management described is more important than performing endoscopy to determine a specific etiology. Fluids, blood, platelets, and plasma are indicated in all forms of severe GI bleeding if there is a coagulopathy. More than 80% of GI bleeding cases will stop spontane- ously with appropriate fluid resuscitation, irrespective of the etiology. Endoscopy is performed later to determine the etiology.
Acute Bleeding. For acute bleeding, fluid resuscitation should be performed as described. The hematocrit should be maintained at ≥30% in older patients and those who may have coronary artery disease. Younger patients will form their own reticulocytes and make their own blood over a few days and do not need to be transfused, unless their hematocrit is closer to 20%.
Patients with gastritis or the possibility of ulcer disease should be treated with PPIs empirically until a definitive diagnosis can be made. H2 blockers have no efficacy in acute GI bleeding.
Esophageal varices are treated with octreotide during acute episodes of bleeding in order to lower portal pressure. If this is ineffective, emergency endoscopy should be performed to place bands around the bleeding varices. Sclerotherapy will also stop acutely bleeding varices, but there is a much higher complication rate later on, such as stricture formation. If banding is not effective in stopping an acutely bleeding esophageal varix, then TIPS (transjugular intrahepatic portosystemic shunting) should be performed. A catheter is placed into the jugular vein and guided radiographically through the liver to form a shunt between the systemic circulation in the hepatic vein and the portal circulation through the portal vein. TIPS has largely replaced the need to surgically place the shunt. The most common, long-term complication of TIPS is worsening of hepatic encephalopathy.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
114
Chapter 4 ● Gastroenterology
A Blakemore tube to tamponade the site of bleeding in the stomach or esophagus is rarely used and is only a temporary bridge to surgery.
Propranolol is a nonselective beta-blocker used in the long-term management of portal hypertension to decrease the frequency of bleeding. Everyone with varices from portal hypertension and cirrhosis should be on a beta-blocker.
Pathogenesis. The most common causes of upper GI bleeding are ulcer disease, gastritis, Mallory-Weiss syndrome, esophagitis, and gastric cancer. Variceal bleeding is common in those with portal hypertension from cirrhosis. By definition, upper GI bleeding is defined as bleeding occurring proximal to the ligament of Treitz, which anatomically separates the duodenum from the jejunum. If there is a history of abdominal aortic aneurysm repair in the past 6 months to a year, think about an aortoenteric fistula.
Lower GI bleeding is most commonly caused by diverticulosis, angiodysplasia (also know as AVM or vascular ectasia), hemorrhoids, cancer, and inflammatory bowel disease.
Clinical presentation. Generally, lower GI bleeding presents with red blood in the stool, and upper GI bleeding presents with black stool, or melena.
Upper GI bleeding can also give hematemesis if the volume of bleeding is high enough. About 10% of cases of red blood from the rectum can be from an upper GI source. This can happen if the volume of bleeding is so high that the blood is rapidly transported to the bowel without the time for it to oxidize and turn black. In upper GI bleeding, occult blood–positive brown stool can occur with as little as 5 to 10 mL of blood loss. The same is true of “coffee-ground” emesis. Melena develops when at least 100 mL of blood have been lost.
Diagnosis. Endoscopy is the most accurate test to determine the etiology of both upper and lower GI bleeding. Barium studies are always less accurate. You also cannot biopsy unless endoscopy is performed.
Occasionally, in lower GI bleeding, endoscopy will not reveal the etiology even when there is active bleeding. A nuclear bleeding scan can detect low volume bleeds 0.1–0.5 mL/min. Red cells from the patient are tagged with technetium and reinjected back into the patient. These tagged cells are then detected to determine the site of bleeding.
Angiography is rarely used in the evaluation of lower GI bleeding because it needs a higher volume of blood loss >0.5 mL/min compared with the tagged nuclear scan. Angiography, however, is useful in extremely high-volume bleeding in which so much blood is coming out that endoscopy cannot see the source. It may then be used prior to either embolization of the site of the bleeding or hemicolectomy. Angiography can also help guide the occasional use of a local vasopressin injection in the control of severe lower GI bleeding.
Note
Consider the treatment, not the etiology, first when a patient is experiencing GI bleed.
Note
Lower GI bleeding presents with red blood in the stool, whereas upper GI bleeding presents with black stool.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
115
USMLE Step 2 l Internal Medicine
Clinical Pearl
Always consider gallstone pancreatitis and rule it out by U/S, even in patients with history of alcohol use.
Despite all of these methods, an etiology of GI bleeding cannot be determined in about 5% of patients. This is often because the upper endoscope only goes as far as the ligament of Treitz, and the lower endoscope only reaches just past the ileocecal valve. When both of these modalities are unrevealing, the most likely source of the bleeding is in the small bowel. The small bowel is very difficult to visualize, and barium studies are inaccurate. The newest modality to visualize the small bowel is capsule endoscopy, in which a patient swallows a capsule with an electronic camera that can transmit thousands of images to a receiver near the patient. This will allow anatomic localization of the lesion.
Virtual endoscopy is a CT scan used to try to detect cancer without the need of endoscopy. Virtual endoscopy lacks both sensitivity and specificity to detect causes of GI bleed, and therefore should not be ordered for this purpose.
Clinical Recall
Which of the following colonic conditions requires additional colonoscopy screening?
Answer: D
Acute pancreatitis is inflammation of the pancreas due to premature activation of trypsinogen into trypsin while still in the pancreas (common pathway of most causes of pancreatitis). This results in autodigestion of the pancreas. Circulating cytokines can lead to many complications.
The majority of cases of pancreatitis are caused by alcoholism and gallstones. Other causes include:
Medications such as valproate, pentamidine, didanosine (DDI), azathioprine, and sulfa derivatives, e.g., sulfamethoxazole/trimethoprim and thiazide diuretics
Hypercalcemia
Hypertriglyceridemia, where elevated triglycerides are broken down to fatty acids, causing inflammation of the biliary tract and eventual pancreatitis
Endoscopic retrograde cholangiopancreatography (ERCP), presumably because of back pressure from injection of the contrast material into the ductal system; most patients who have pancreatic injury from ERCP have just an asymptomatic increase in amylase and only 2–8% actually develop symptomatic pancreatitis
Trauma and various viruses, such as mumps
Clinical Presentation. The classic presentation of acute pancreatitis is midepigastric pain with tenderness, nausea, and vomiting. The pain typically radiates straight through to the back. When
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
116
Chapter 4 ● Gastroenterology
extremely severe, pancreatitis can mimic many of the features of septic shock, with fever, hypotension, respiratory distress from ARDS, elevation of white cell count, and a rigid abdomen.
Diagnosis. To diagnose, there must be 2 of the following 3 features:
Acute onset of upper abdominal pain
Amylase or lipase >3x the upper limit of normal
Evidence on imaging
The initial tests remain as amylase and lipase (lipase is more specific to the pancreas than is amylase). CT scan should not be given routinely; only do if pancreatitis is severe, lasts longer than 48 hours, or complications are suspected.
The most important sign of severe pancreatitis and poor prognosis is elevated or raising BUN. Hypertriglyceridemia can give a falsely normal amylase and lipase levels.
The most accurate test to determine the severity of pancreatitis is the CT scan, which is more accurate than a sonogram for detecting the presence of inflammation, necrosis, pseudo-cysts, abscesses, and ductal stones. The APACHE score is also used to stratify acute pancreatitis.
The single most accurate test for the detection of biliary and pancreatic ductal pathology is
ERCP.
Treatment. Treat with aggressive IV fluids (250–500 mL/hr), bowel rest, and pain medication (use morphine, as it does not constrict the sphincter of Oddi, and never use meperidine [black box warning label for seizures]).
Aggressive IV fluids are most beneficial in first 12–24 hours and may be harmful after that time; reduce after 24 hours (Lactated Ringer’s is preferred over normal saline based on clinical data).
Resume oral feeding as soon as pain and nausea resolve; no need to wait.
Administer antibiotics only if evidence of infected necrosis based on biopsy;
Do ERCP only if ascending cholangitis or nonresolving biliary obstruction, as it can otherwise worsen pancreatitis.
For gallstone pancreatitis, do cholecystectomy prior to discharge.
For severe acute pancreatitis that does not resolve within 72 hours, give enteral feeding via NGT or nasojejunal feeds, not total parental nutrition. Data shows that enteral feeding improves mortality (vs parental). Do not keep patient NPO after 72 hours, as that leads to increased risk for sepsis and death.
When pancreatitis is very severe, e.g., >30% necrosis visible on CT, the risk of infected and hemorrhagic pancreatitis markedly increases.
Severe necrosis, particularly when there is persistent fever, is also an indication to perform a percutaneous needle biopsy of the pancreas. If infection of the pancreas accompanies the necrosis, imipenem and urgent surgical debridement are indicated.
Antibiotics should not be routinely given for pancreatic necrosis; they should be reserved for those with proven infection.
If patient does not improve or deteriorates 7–10 days after presentation, perform CT-guided fine-needle aspiration.
Note
Signs of Severe Necrotizing Pancreatitis
Cullen sign: blue discoloration around umbilicus → due to hemoperitoneum
Turner’s sign: bluish purple discoloration of the flanks → tissue catabolism of Hb.
Note
IV fluid intake in large volumes is the most important management of acute pancreatitis; it must be given in the first 12–24 hours.
Note
Other complications of pancreatitis include:
Ascites (high in amylase)
Pleural effusion (transudate,
increased amylase)
Splenic vein thrombosis (think when there are gastric varices but no esophageal varices)
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
117
USMLE Step 2 l Internal Medicine
In stable patients with infected necrosis, the preferred approach is to initiate antibiotics and to ideally delay drainage procedures for at least 4 weeks to allow the collection to become encapsulated, which facilitates drainage.
Pseudocysts develop only 2–4 weeks after the episode of pancreatitis; drain them if there is pain, fistula formation, or rupture (asymptomatic pseudocysts need not be drained).
Figure 4-3. Pancreatic Pseudocyst
Type I presents with painless jaundice or acute pancreatitis (rare).
Elevated IgG4
IgG4-related disease (IgG4-RD) is a chronic inflammatory condition characterized by tissue infiltration with lymphocytes and IgG4-secreting plasma cells various degrees of fibrosis (scarring) involving multiple organs.
Multiple autoimmune conditions are seen, including Sjögren syndrome, primary sclerosing cholangitis, hepatomegaly interstitial nephritis (enlarged kidneys) and inflammatory bowel disease.
Type II presents with chronic pancreatitis.
No systemic disease
Normal IgG4
Need biopsy to diagnose
Treatment. Steroids are used.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
118
Chapter 4 ● Gastroenterology
LIVER DISEASE AND CIRRHOSIS
Cirrhosis develops when there is chronic and severe inflammation of the liver for an extended period of time. The regenerative capacity of the liver is enormous; however, over a long time, fibrosis will develop. And when at least 70–80% of liver function has been lost, the synthetic capacity of the liver is diminished.
In the United States the most common cause of cirrhosis is alcohol. Other causes include primary biliary cirrhosis, sclerosing cholangitis, alpha-1 antitrypsin deficiency, hemochroma- tosis, and Wilson disease.
The complications of cirrhosis are due to portal hypertension. Portal hypertension develops because of mechanical factors of fibrosis and regenerative liver nodules, as well as increased intrahepatic vascular resistance in increased portal inflow. The high pressure in the portal vein is decompressed through collateral portosystemic shunts that occur in the esophagus and the stomach.
Clinical Presentation. Despite the etiology, all forms of cirrhosis have the following features:
Low albumin
Portal hypertension
Esophageal varices
Ascites
Peripheral edema
Elevated prothrombin time (prolonged due to loss of ability to synthesize clotting factors)
Splenomegaly
Thrombocytopenia
Spider angiomata
Palmar erythema
Asterixis
Jaundice (possible)
All of the clotting factors are made in the liver (except factor VIII and von Willebrand factor, made by endothelial cells). If factor VIII is low in addition to other factors, it is not liver disease—think disseminated intravascular coagulation (DIC), which is made in the vascular endothelial cells.
Ascites is the result of portal hypertension. A paracentesis is a sample of the ascitic fluid obtained by needle through the anterior abdominal wall. A paracentesis is used to exclude infection, as well as to determine the etiology of the ascites if it is not clear from the history.
Spontaneous bacterial peritonitis (SBP) is an idiopathic infection of ascites. The Gram stain is rarely positive because the density of microorganisms is so low. Although culture of the fluid is the most specific test, do not wait for the results to make a decision as to whether to give
antibiotics. The presence of >250/mm3 neutrophils are the criteria to determine the presence
of infection. Cefotaxime or ceftriaxone is the drug of choice for SBP, and albumin infusion
will decrease the risk of hepatorenal syndrome.
Note
While alcohol is the most common cause of cirrhosis in the United States, the most common reason to need a liver transplant is chronic hepatitis C.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
119
USMLE Step 2 l Internal Medicine
Note
Although a culture of the ascitic fluid is the most specific test for SBP, do not wait for culture results when considering antibiotics.
Clinical Pearl Remember to subtract the lower number (ascites
albumin) from the higher
number (serum albumin) when calculating SAAG.
Note
For HCC, do U/S screening every 6 months.
Once a patient has SBP, the risk of recurrence is 70% per year. Therefore, treat the patient with norfloxacin or ciprofloxacin daily (indefinitely) to prevent recurrence. Also, all beta-blockers must be stopped due to increased mortality.
Serum-Ascites Albumin Gradient. Normally, the ascitic fluid albumin level is less than the serum level. The difference between them is referred to as the serum-ascites albumin gradient (SAAG). Total protein in the ascites fluid must also be checked.
When SAAG ≥1.1, portal hypertension, the cause of ascites is increased hydrostatic pressure. The ascites total protein will tell you the cause of the elevated hydrostatic pressure.
When SAAG ≥1.1 and total protein >2.5 g/dL, heart failure, Budd-Chiari (check JAK2 to work up P. vera).
When SAAG <1.1, it means the ascitic fluid albumin level is high. Cancer and infections gen- erally produce SAAG <1.1.
When SAAG <1.1 and total protein <2.5 g/dL, there is nephrotic syndrome (protein is lost in urine).
When SAAG <1.1 and total protein >2.5 g/dL, there is carcinomatosis (think ovarian), Tb (do peritoneum biopsy, which will have high lymphocytes in ascites, too)
Treatment. There is no specific therapy to reverse cirrhosis; one can only manage the complications and treat the underlying causes. (A complication to consider is hepatocellular carcinoma.) Edema and fluid overload in third spaces, such as ascites, are managed with diuretics (spironolactone most useful in cirrhosis). That is because cirrhotics have intravascular volume depletion, producing a high aldosterone state (secondary hyperaldosteronism). Furosemide is commonly added after spironolactone to increase volume removal. Giving furosemide without spironolactone will lead to hypokalemia, which can cause encephalopathy.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
120
Chapter 4 ● Gastroenterology
Propranolol is used to prevent bleeding in portal hypertension and varices. Discontinue after SBP, refractory ascites, or hypotension.
Encephalopathy is managed with lactulose, a nonabsorbed disaccharide that bacteria metabo- lize in the colon, making it more acidic. This converts the NH3 to NH4+, or ammonia to ammonium. Ammonium is not absorbed very well, and that leads to an overall increased excretion of ammonia from the body.
If patient is not responsive, add rifaximin, an RNA polymerase blocker not absorbed which changes the flora of the GI tract. Neomycin is not used for encephalopathy due to renal toxicity.
Hepatorenal syndrome is diagnosed by the following:
Increased creatinine >1.5 mg/dL over days to weeks
Lack of response to albumin infusion for 48 hours (stop diuretics, too)
Exclusion of other causes of AKI (sepsis); must have normal urine (no blood or protein)
Type 1 is more severe with doubling of creatinine in 2 weeks.
Type 2 is less severe with more gradual increase in creating.
Treat with midodrine, octreotide and albumin (must give for 48 hours first to rule out pre- renal). If it fails, perform liver transplant.
Although vitamin K is often given because of the elevated prothrombin time, it is not effective because the liver is unable to synthesize clotting factors regardless of how much vitamin K is present.
Primary biliary cirrhosis is an idiopathic autoimmune disorder that is often seen in middle- aged women. Bilirubin does not elevate until the disease is extremely far advanced (5–10 years). There is a strong association with other autoimmune diseases, such as Sjögren syn- drome, rheumatoid arthritis, and scleroderma.
Clinical Presentation. The most common symptoms are fatigue and pruritus. At least 30% of patients are asymptomatic but are found to have an elevated alkaline phosphatase when measured for other reasons. Osteoporosis and hypothyroidism are found in 20–30% of patients.
Diagnosis. The transaminases are often normal. The most common abnormality is elevated alkaline phosphatase and gamma glutamyl transpeptidase (GGTP). Total IgM levels are also elevated. The most specific blood test is the antimitochondrial antibody.
Biopsy is always the best way to diagnose liver disease. It is the only test more specific than antimitochondrial antibodies.
Treatment. There is no specific therapy for primary biliary cirrhosis. Steroids will not help. Ur- sodeoxycholic acid is primary treatment. Cholestyramine will help with the pruritus, as will ultraviolet light. Liver transplant for late stage PBC may also be considered.
Note
Give octreotide during a bleed, then band. Give propranolol after the bleed to prevent another bleed.
Note
In a patient with ascites, stop ACE-I, ARBs, and NSAIDs.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
121
USMLE Step 2 l Internal Medicine
Note
Primary sclerosis cholangitis is the only chronic liver disease in which a liver biopsy is not the most accurate test.
Note
Ferritin is elevated in liver disease and alcoholics.
Transferrin saturation is the best screening test; if it is negative, diagnosis is not hemochromatosis.
Primary Sclerosis Cholangitis
Primary sclerosis cholangitis is an idiopathic disorder of the biliary system most commonly associated with inflammatory bowel disease (IBD). Although it is more often found with ulcerative colitis, it can also occur with Crohn’s disease. Cancer of the biliary system can develop in 15% of patients from the chronic inflammation.
Clinical Presentation and Diagnosis. The presentation and general lab tests are typically the same as those for primary biliary cirrhosis, except that the antimitochondrial antibody test will be negative. The most specific test for primary sclerosis cholangitis is ERCP or MRCP: “string of beads of MRCP or ERCP.” This is the only chronic liver disease in which a liver biopsy is not the most accurate test.
Treatment. Treat with endoscopic therapy for strictures; cholestyramine for itching.
Hemochromatosis is one of the most common inherited genetic diseases. There is an overab- sorption of iron in the duodenum, leading to iron buildup in tissue throughout the body, thus resulting in chronic hepatic inflammation and fibrosis. Presentation include the following:
Arthralgias, osteoarthritis in the MPC joints, osteophytes on x-ray, skin hyperpig- mentation, diabetes, and secondary hypogonadism (decreased libido and impotence)
Vibrio vulnificus and Yersinia infections occur with increased frequency because of their avidity for iron.
Screening for hemochromatosis is made with elevated transferrin saturation >55%. Ferritin is also elevated. C282Y homozygous and C282Y/H63D are diagnostic of hemochromatosis and do need a liver biopsy for diagnosis.
The most accurate test is a liver biopsy.
Treatment. Phlebotomy is used to remove large amounts of iron from the body—it removes far more iron than do the chelating agents deferoxamine and deferasirox. Deferoxamine and deferasirox are used only for those who cannot undergo phlebotomy.
Wilson Disease
Wilson disease is an autosomal recessive disorder leading to a diminished ability to excrete copper from the body. There is also increased copper absorption from the small intestine.
Copper builds up in the liver, brain, and cornea.
Basal ganglia dysfunction contributes to the movement disorder which develops.
Psychiatric disturbance is seen in 10% of patients.
Kayser-Fleischer rings are found in the eye on slit-lamp examination.
Tremor and Parkinson’s result in 35% of patients.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
122
Chapter 4 ● Gastroenterology
Fanconi syndrome and type II proximal renal tubular acidosis develop due to copper deposition in the kidney.
Hemolytic anemia may be present (copper destabilizes the RBC membranes).
The most specific blood test for diagnosis is decreased ceruloplasmin but that alone is not enough. There is also increased urinary copper. The single most specific test is liver biopsy, which will demonstrate increased copper deposition in the liver. Occasionally, hemolytic anemia is seen when copper levels go high and are toxic to the red cells.
Treatment. Penicillamine and trientine are copper chelators. Oral zinc interferes with copper absorption. Steroids will not help. Liver transplantation is curative.
Alpha-1 Antitrypsin Deficiency
Alpha-1 antitrypsin deficiency (AATD) is an autosomal recessive condition which causes a low level (or no level) of alpha-1 antitrypsin (AAT) in the blood. The condition is found in all ethnic groups but occurs most often in whites of European ancestry. AAT protects the lungs so they can have normal function. AAT is made in the liver; without enough of it, the lungs become damaged, leading to emphysema.
Everyone has 2 copies of the gene for AAT and receives 1 copy of the gene from each parent.
Patients with AATD have 1 normal copy and 1 damaged copy, or they have 2 dam- aged copies.
Most patients with 1 normal gene can produce enough AAT to live healthy lives, especially if they do not smoke.
Those with 2 damaged copies of the gene are generally not able to produce enough AAT, leading them to have more severe symptoms.
The most prominent finding is emphysema developing at a young age in a nonsmoker. Approxi- mately 15% of those with AATD develop cirrhosis. Large amounts of abnormal AAT are made in the liver; nearly 85% of this protein accumulates in the liver causing inflammation and eventually, fibrosis.
Diagnosis. Testing for AATD, using a blood sample from the individual, is simple, quick and highly accurate. Three types of tests are usually done on the serum sample:
Alpha-1 genotyping, which examines a person’s genes and determines his genotype
AAT PI type of phenotype test, which determines the type of AAT protein a person has
AAT level test, which determines the amount of AAT in a person’s blood
Treatment. There is no specific therapy for the liver disease. Those with emphysema should receive replacement of the enzyme and stop smoking.
Chronic Hepatitis B and C
Hepatitis B and C are transmitted by blood products, needlestick injury, and sexual contact. Injection drug use is also strongly associated with both viruses.
Hepatitis C virus causes 60−70% of cases of chronic hepatitis; at least 80% of acute hepatitis C cases become chronic
Note
A patient presenting with choreoathetoid movements and psychosis gives the clue to perform the slit-lamp examination. Kayser-Fleischer rings are then found, confirming the diagnosis of Wilson disease.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
123
USMLE Step 2 l Internal Medicine
About 10% of hepatitis B cases, sometimes with hepatitis D coinfection, become chronic; hepatitis D does not occur by itself but rather only as a coinfection with hepatitis B
Rarely, hepatitis E virus causes chronic hepatitis in those with weakened immune systems (organ transplant treatment, chemotherapy for cancer, HIV infection)
Hepatitis A virus does not cause chronic hepatitis
Hepatitis C is the most common cause of chronic hepatitis in the United States; it is also the most common cause of cirrhosis and hepatocellular carcinoma.
Most patients are asymptomatic until the disease is very far advanced.
Diagnosis.
To confirm hepatitis B: persistence of hepatitis B surface antigen >6 months (though it takes years for cirrhosis to develop)
Remember, in chronic hepatitis B, the hep B surface antibody is negative.
To confirm hepatitis C: finding an antibody to hepatitis C, and then finding an elevation of the viral load by PCR methods
Single most accurate test to diagnose the extent of liver disease is liver biopsy
Treatment. Chronic hepatitis B is treated with interferon, lamivudine, entecavir, telbivudine, or adefovir. Combining these agents does not lead to increased efficacy.
Chronic hepatitis C is now cured with the new combination antiviral drugs. The most commonly used is ledipasvir/sofosbuvir (trade name Harvoni), a 2-drug combination. It is administered as a 1x/ daily pill containing the viral NS5A inhibitor ledipasvir and a nucleotide inhibitor of the viral RNA polymerase, sofosbuvir. Taken daily for 8–12 weeks, it provides cure rates of 94−99% in those infected with genotype 1 (the most common form of hepatitis C in the United States and some European countries), irrespective of the presence or absence of liver cirrhosis or prior unsuccessful treatment. It has also been evaluated for the treatment of infection with other hepatitis C genotypes and has shown promising results in genotypes 3 and 4.
Which of the following is not a cause of cirrhosis?
Alpha-1 antitrypsin deficiency
Budd-Chiari syndrome
Hepatitis A
Hemochromatosis
Primary biliary cirrhosis
Answer: C
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
124
ChCaaprtdeiroTloitglye #5
Learning Objectives
Outline a differential diagnosis and diagnostic plan for patients with acute chest pain or chest discomfort
List the causes of and treatment for heart rate and rhythm disturbance
Describe the physiology of valvular disease and CHF, and describe the mechanism of action of appropriate treatments
Give an overview of presentation, epidemiology, and management of ischemic heart disease, acute coronary syndrome, myocardial disease, and pericardial disease
Describe the most common medications used to treat cardiovascular disease and their most serious or common side effects
Chest pain or discomfort is one of the most common complaints that brings patients to the physician’s office or emergency department. Patients presenting with this symptom may have an underlying cause that is benign and requires only moderate analgesic medication, or they may have a life-threatening condition such as acute myocardial ischemia or aortic dissection that mandates prompt diagnosis and treatment. In the evaluation of chest pain, the focus should be on excluding the more serious conditions.
History
Assessing the setting in which the chest pain occurs is one of the most important aspects of the evaluation. The healthy 26-year-old medical resident with chest pain that occurred after on-call is unlikely to have cardiovascular disease, no matter the quality or duration of chest pain. The
year-old man who has type 2 diabetes and dyslipidemia with chest discomfort of any type has a much higher probability for cardiac-related chest pain.
Overall, the chest pain history is more useful than the physical examination. Important aspects of the history include duration, quality, location, radiation, frequency, alleviating or precipitating factors (especially exercise), and associated symptoms.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
125
USMLE Step 2 l Internal Medicine
For both stable angina and acute coronary syndromes, the quality of chest pain is described by the patient as “tightness,” “heaviness,” or “pressure,” but symptoms resembling acute abdomen (pain in upper abdomen, nausea) are not uncommon. Nausea and vomiting are sometimes the main symptoms in inferoposterior wall ischemia (also, vagal reflexes may cause bradycardia and hypotension, presenting as dizziness or fainting).
“Sharp” or “knife-like” chest pain and pain which the patient can pinpoint to an “exact area” are less likely to be related to ischemia or infarction, especially if the chest pain is reproduced by changes in position or palpation.
Myocardial infarction is associated with pain that lasts >20–30 minutes in duration.
Response of chest pain to nitroglycerin (within a few minutes) is most consistent with transient ischemia or esophageal spasm. Chest pain that worsens with nitroglycerin sometimes occurs with gastroesophageal reflux disease. The response to nitroglycerin is not enough to confirm coronary disease as the cause of chest pain.
Acute coronary syndromes in women present with atypical symptoms: dyspnea, shortness of breath, fatigue. This may be due to the older age group in which myocar- dial ischemia and infarction occur in women.
One of the most important parts in a chest pain examination is the “initial impression.” Diaphoresis, tachypnea, and anxious expression should alert you to a potentially life- threatening process. Tachycardia and tachypnea are both nonspecific but occur in almost all cases of pulmonary embolism.
Check BP in both arms: a difference of >20 mm Hg systolic suggests aortic dissection and is present in ~70% of cases.
Hypotension may suggest massive pulmonary embolism or cardiac shock.
Fever may suggest pneumonia or mediastinitis (esophageal rupture) as the cause of chest pain.
Evidence of atherosclerosis (corneal lipid rings, narrowed retinal arteries, and pigment and hair changes in the legs) is commonly seen in patients with coronary syndromes.
Inspect the chest wall for tender areas, respiratory motion, respiratory retractions, or accessory muscle use. If the tender area corresponds to the location of the patient’s pain and palpation exactly reproduces the pain, consider musculoskeletal chest pain as the cause of chest pain.
Abnormal heart sounds and new murmurs are commonly found in certain chest pain syndromes. Wide physiologic splitting of the second heart sound (splitting wider with inspiration) can be found in right bundle branch block or in right ventricular infarction. New paradoxical splitting is most often due to left bundle branch block (LBBB), or anterior or lateral infarction. A new fourth heart sound can occur with angina or infarction. An S3 is more likely due to underlying heart failure. A new murmur may be significant: aortic regurgitation occurs in over half of patients with aortic dissection, while mitral regurgitation can occur in patients with angina or infarction and is due to papillary muscle dysfunction.
The lungs should be auscultated for crackles and asymmetrical breath sounds. Asymmetry of breath sounds may be found in patients with spontaneous pneumothorax. Absent lung sounds also may occur in pneumothorax and pleural effusions.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
126
Chapter 5 ● Cardiology
The extremities should be examined for pulses, edema, calf tenderness, and signs of atherosclerotic vessel disease. Absence of pedal pulses may occur in aortic dissection. Any swelling of the legs, especially if unilateral, raises the odds of pulmonary embolism as the cause of chest pain.
Testing
All patients with chest pain should have a 12-lead electrocardiogram (ECG) since the ECG is the single most important test for the evaluation of the cause of chest pain. The ECG should be done immediately after initial stabilization and taking of vital signs.
Most patients with myocardial infarction will have an abnormal initial ECG:
50% with acute MI will have diagnostic findings (ST elevation or Q waves)
35% will have findings consistent with ischemia (ST depression and/or T wave inversion)
In patients presenting with acute chest pain who have normal ECG, the chance of acute MI is much less than 10% (in some studies 1–2.6%).
An abnormal ECG can be seen in many non-cardiac conditions (pulmonary embo- lism, electrolyte abnormalities, aortic dissection).
In interpreting the ECG, make every effort to obtain previous ECGs, so that abnormalities can be compared with those on the old tracing. Any ECG finding is assumed to be new unless proven otherwise by an old ECG (if one is available). Also, in patients with acute coronary syndromes, the ECG is the sole test required to select patients for emergency reperfusion.
Serum cardiac biomarker determinations play a vital role in the evaluation of patients who present with acute chest pain and in the diagnosis of acute myocardial infarction. Serum markers such as aspartate transaminase, lactate dehydrogenase, and lactate dehydrogenase subforms no longer are used because they lack cardiac specificity and their delayed elevation precludes early diagnosis. Creatine kinase (CK) is found in striated muscle and tissues of the brain, kidney, lung, and GI tract. This widely available marker has low sensitivity and specificity for cardiac damage. Furthermore, CK levels may be elevated in a number of noncardiac conditions, including trauma, seizures, renal insufficiency, hyperthermia, and hyperthyroidism. Currently, the CK marker largely has been replaced by cardiac troponins and CK-MB.
CK-MB isoenzyme: CK-MB is cardiac specific and is useful for the early diagnosis of acute myocardial infarction. CK-MB typically is detectable in the serum 4–6 hours after the onset of ischemia, peaks in 12–24 hours, and normalizes in 2–3 days.
Like the CK level, the peak CK-MB level does not predict infarct size; however, it can be used to detect early reinfarction. Serial CK-MB levels commonly are obtained at admission to the emergency department and are repeated in 6–12 hours.
CK-MB subforms: CK-MB may be further characterized into subforms (or isoforms).
CK-MB2 is found in myocardial tissue, and CK-MB1 is found in plasma. The CK-MB subform is not routinely used.
Cardiac troponins: Troponins (T, I, C) are found in striated and cardiac muscle. Because the cardiac and skeletal muscle isoforms of troponin T and I differ, they are known as the “cardiac troponins.” They are the preferred markers for the diagnosis of myocardial injury. Troponin T and I generally have similar sensitivity and specificity for the detection of myocardial injury.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
127
USMLE Step 2 l Internal Medicine
Unlike troponin I levels, troponin T levels may be elevated in patients with renal disease, polymyositis, or dermatomyositis.
The cardiac troponins typically are measured at emergency department admission and repeated in 6–12 hours. Patients with a normal CK-MB level but elevated troponin levels are considered to have sustained minor myocardial damage, or microinfarction, whereas patients with eleva- tions of both CK-MB and troponins are considered to have had acute myocardial infarction. The cardiac troponins may remain elevated up to 2 weeks after symptom onset, which makes them useful as late markers of recent acute myocardial infarction.
An elevated troponin T or I level is helpful in identifying patients at increased risk for death or the development of acute myocardial infarction. Increased risk is related to the high serum troponin levels. The troponins also can help identify low-risk patients who may be sent home with close follow-up. Those with a normal or nearly normal ECG and a normal troponin I test 6 hours after admission had a very low risk of major cardiac events (0.3%) during the next 30 days.
Myoglobin levels begin to rise as early as 1–4 hours after the onset of pain. Normal myoglobin at 4 hours has a very high negative predictive value.
5 10 15
Figure 5-1. Progression of Cardiac Enzyme Serum Levels
Chest x-ray should be obtained on patients with chest pain; it may show pneumothorax, pneumomediastinum (i.e., from esophageal rupture), pleural effusion, or infiltrates. Aortic dissection can cause widening of the mediastinum. Subtle findings such as loss of lung volume or unilateral decrease in vascular markings may suggest pulmonary embolism.
Especially if a noncardiac diagnosis is suspected, arterial blood gases, BNP, and CT angiogram may be helpful for evaluating acute chest pain.
Causes of Chest Pain
Aortic Dissection. Pain is sharp, tearing, and extremely severe; typically radiates to back; loss of pulses or aortic insufficiency often develop.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
128
Chapter 5 ● Cardiology
On chest x-ray, mediastinum is widened
MI may occur if dissection extends into coronary artery
Diagnosis confirmed by MRI, CT scan, or transesophageal echocardiogram
Pulmonary Embolism. Dyspnea, tachycardia, and hypoxemia are prominent; pain is usually pleuritic, especially when pulmonary infarction develops.
EKG is usually nonspecific but may show S wave in lead I, Q wave in lead III, or inverted T wave in lead III
Diagnosis confirmed by CT angiogram
Pericarditis. May be preceded by viral illness; pain is sharp, positional, pleuritic, and relieved by leaning forward.
Pericardial rub often present
Table 5-1. Differential Diagnosis of Conditions Causing Chest Pain
Costochondritis | Pain exacerbated with inspiration; reproduced with chest wall palpitation |
Hiatal hernia | |
GERD | |
Peptic ulcer | |
Gallbladder disease | |
Cardiovascular Disorders | |
Myocardial infarction | |
Aortic stenosis | Typical systolic ejection murmur |
Myocarditis | Pain is usually vague and mild if present |
Pericarditis | Pain is sharper, pain worse with lying down and relieved by sitting up |
Dissecting aortic aneurysm | Pain is sharp, tearing, often occurs in back |
Mitral valve prolapse | Transient pain, midsystolic click murmur, and young female with no risk factors |
Pulmonary Disorders | Differentiating Features |
Pulmonary embolus-infarction | Tachypnea, dyspnea, cough, pleuritic pain, hemoptysis |
Pulmonary hypertension | Signs of right ventricle (RV) failure |
Pneumothorax | Sudden onset of pain and dyspnea |
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
129
USMLE Step 2 l Internal Medicine
Myocarditis. May be preceded by viral illness; pain is generally vague and mild if present; total CK and MB fraction of CK (CK-MB) are often elevated; conduction abnormalities and Q waves may occur.
Musculoskeletal Disorders. Most common cause of chest pain. Includes costochondritis, cervical osteoarthritis, radiculitis; pain is atypical, stabbing, localized, may be pleuritic; reproduced by motion or palpation; EKG changes absent.
GI Disorders. Esophageal reflux is often made worse with recumbency or after meals, may be associated with regurgitation and relieved by antacids; episodes of spasm may be brought on by cold liquids, relieved by nitroglycerin, and may closely resemble angina or infarction; diagnosis may be confirmed by upper endoscopy or esophageal manometry. Peptic ulcer disease, pancreatitis, and cholecystitis may occasionally mimic infarction; abdominal tender- ness is present, with radiation to back and elevated amylase in pancreatitis; sonography can confirm cholecystitis.
Pneumothorax. Onset abrupt with sharp pleuritic chest pain and dyspnea; breath sounds absent; chest x-ray confirms.
Pleuritis. Pain is sharp and increases on inspiration; friction rub or dullness may be present; other respiratory symptoms and underlying pulmonary infection usually present.
Which of the following is the single most important test in the management of chest pain?
Answer: D
ISCHEMIC HEART DISEASE
Ischemic heart disease (IHD), also known as coronary heart disease, is an imbalance in coronary oxygen demand and supply resulting from insufficient blood flow. In nearly all cases, the reduction in blood flow is caused by coronary atherosclerotic disease.
When the atherosclerotic plaque ruptures, there is superimposed thrombus formation that acutely occludes the artery; this is the most common cause of life-threatening acute coronary syndromes.
Rarely, other abnormalities may occur (coronary artery embolism, coronary artery spasm, coronary arteritis, and coronary artery dissection) which may cause IHD in the absence of atheroma formation.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
130
Chapter 5 ● Cardiology
IHD is one of the most prevalent diseases in society, and those affected are likely to die from their disease (though age-specific deaths have declined over the past 30 years). As part of a systemic process that involves all arteries in the body, it is an insidious process that begins in early adulthood with fatty streaks; these lesions progress into plaques and thrombus formation in middle age.
Ischemic Heart Disease
Clinically Silent
(asymptomatic)
Symptomatic
Acute coronary syndromes:
Unstable angina
Non ST-segment elevation MI
ST-segment elevation MI
Atherosclerotic
plaque
Ruptured
plaque
atherosclerotic plaque Thrombosis formation
Atherosclerotic
plaque
Figure 5-2. Ischemic Heart Disease
The more risk factors a person has, the greater the chance that he will develop heart disease. Also, the greater the level of each risk factor, the greater the risk. For example, a person with total cholesterol 260 mg/dL has a greater risk than someone with total cholesterol 220 mg/dL, even though all people with total cholesterol ≥220 mg/dL are considered high risk.
Major Modifiable Risk Factors
Elevated cholesterol levels: The risk of IHD rises as blood cholesterol levels increase. The con- centrations of lipid fractions, especially low-density lipoprotein (LDL) and high-density lipoprotein (HDL), are also important. LDL cholesterol is the single most important subgroup that carries risk for IHD, although there are several other abnormalities
that increase coronary risk: low HDL cholesterol, hypertriglyceridemia, increased
total-to-HDL-cholesterol ratio and increased lipoprotein A. When other risk factors (such as high blood pressure and tobacco smoke) are present, this risk increases even more.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
131
USMLE Step 2 l Internal Medicine
Proof of the importance of serum cholesterol has come from randomized trials, which showed that reductions in total LDL levels reduce coronary events and mortality.
Tobacco: Cigarette smoking is an important factor for IHD because a smoker’s risk of heart attack is >2x that of a nonsmoker. Cigarette smoking also acts with other risk factors (hypertension, dyslipidemia) to greatly increase the risk for IHD.
Cigar or pipe smokers have a higher risk of death from IHD, though less than ciga- rette smokers.
Secondhand smoke or passive smoking increases the risk of heart disease, even for nonsmokers.
The risk for myocardial infarction in those who quit smoking was reduced to that of nonsmokers within 2 years of cessation; the benefits were seen regardless of how long or how much the patient smoked.
Hypertension (HTN): HTN is a well-established risk factor for increase in risk of myocardial ischemia, stroke, kidney failure, and heart failure. Studies in the general population have shown that the risk for cardiovascular events increases at BP >110/75 mm Hg. Systolic BP is as important as diastolic BP in terms of risk for IHD, especially in older patients.
Treatment of HTN to optimal levels reduces the risk of IHD and all cardiovascular events. In fact, data from recent randomized trials suggest that reducing BP below previously recommended levels is beneficial in high-risk patients.
Physical inactivity and exercise: Inactivity and sedentary lifestyle are risk factors for IHD. Exercise of moderate degree has a protective effect against IHD and cardiovascular events. More vigorous activities are associated with more benefits. Physical activity can help increase HDL cholesterol and control diabetes and obesity, as well as help to lower blood pressure.
Obesity: Patients with increased body fat (elevated body mass index), especially if a lot is in the waist area, are more likely to develop heart IHD and stroke. Excess weight raises blood pressure, blood cholesterol, and triglyceride levels, and it lowers HDL cholesterol levels. It can also increase risk for type 2 diabetes by causing insulin resistance.
Studies have shown that loss of as little as 10–20 lb can significantly reduce the risk of cardiovascular disease.
Diabetes mellitus: Elevated blood glucose levels and insulin resistance are associated with IHD and overall cardiovascular events. All-cause mortality in diabetic patients is
comparable to that of all-cause mortality in patients with prior myocardial ischemia; hence, diabetes is now considered an “IHD equivalent.” Even when glucose levels are under control, diabetes greatly increases the risk of IHD. Almost 75% of patients with diabetes die of some form of cardiovascular disease.
There is compelling evidence that aggressive treatment of HTN and cholesterol, as well as tight glycemic control, reduces the risk of cardiovascular events in these patients significantly.
Major Unmodifiable Risk Factors
Age: Four out of 5 people who die of IHD are age ≥65. Also, women who develop myocardial ischemia at older ages have a higher mortality than men within the first few weeks of the cardiac event.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
132
Chapter 5 ● Cardiology
Sex: Men have a greater risk of IHD than women, and overall they develop cardiovascular disease earlier in life.
Heredity: Family history is a significant independent risk factor if there is a family history of premature disease (age <55 in male relative and <65 in female relative).
Minor Contributing Factors
Sex hormones: Men have more heart attacks than women before menopause. Several studies show that the decrease of natural estrogen as women age may contribute to a higher risk of heart disease after menopause.
Stress: Various studies have shown relationship between IHD risk and stress in a person’s life. This may be a true association or just a secondary correlation: for example, people under stress may overeat, start smoking, or be less active than people who are not under stress.
Myocardial Ischemia As a Manifestation of IHD
During ischemia, an imbalance occurs between myocardial oxygen supply and demand. Ischemia may manifest in any of the following ways:
Myocardial ischemia can be caused by increased myocardial oxygen demand, reduced myocar- dial oxygen supply, or both. In the presence of coronary obstruction, an increase of myocardial oxygen requirements caused by exercise, tachycardia, or emotion leads to a transitory imbal- ance. (This condition is called “demand ischemia” and is responsible for most episodes of chronic stable angina.)
In other situations, the imbalance is caused by acute reduction of oxygen supply secondary to marked reduction or cessation of coronary flow as a result of platelet aggregates or thrombi. This condition (“supply ischemia”) is responsible for myocardial infarction (MI) and most episodes of unstable angina (UA). In many circumstances, ischemia results from both an increase in oxygen demand and a reduction in supply.
Angina (Stable Angina)
A 62-year-old man presents with substernal chest pain that occurs with exertion and is relieved by rest. He has been having this on and off for 8 months, and the last episode occurred 3 days ago while he was running to the bus. He has a history of well-controlled diabetes and dyslipidemia. Vital signs, physical examination, and ECG are normal. An exercise stress test shows a 2-mm ST depression.
Stable angina occurs when the myocardium becomes ischemic. This occurs during periods of increased demand for oxygen, such as exercise, or decreased supply, such as hypotension or
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
133
USMLE Step 2 l Internal Medicine
anemia (see demand ischemia, above). Stable angina is typically a substernal pressure lasting 5–15 minutes. It may be accompanied by radiation to the jaw, neck, shoulders, or arms. It is less likely to have the symptoms often associated with MI: sweats, nausea, and shortness of breath. Anginal pain is not typically affected by respiration or by position. Typically, patients with stable angina will have pain after a predictable amount of exertion and will have identical symptoms with each attack.
In certain patients, symptoms other than pain may occur. For example, a profound sense of weakness and breathlessness may be an “angina equivalent.” Atypical symptoms are more likely to occur in the elderly and in diabetics.
The physical exam is usually normal. A new S4 may be heard, suggesting a stiff ventricle due to ischemia.
Most patients with angina will have ECG changes during an attack. Most commonly, ST segment depression is seen. ST segment elevation occurs in variant angina (Prinzmetal angina) where coronary artery spasm is responsible and rarely during ischemia caused by stable angina (where atherosclerotic disease is responsible).
Diagnosis. The exercise treadmill test (exercise stress test) is the most useful test for evalu- ating the cause of chronic chest pain when there is concern about IHD (stable angina).
Exercise stress testing provides a controlled environment for observing the effects of increases in the myocardial demand for oxygen. In order to do an appropriate analysis, a target heart rate must be reached.
Target heart rate is 85% of predicted maximum heart rate: 85% × (220 – patient’s age)
Reaching target heart rate makes test more accurate than if lower heart rate is achieved
Significant fixed stenoses of the coronary arteries will result in ECG evidence of ischemia. Low-grade stenoses (<50%) may not produce sufficient impairment of blood flow to affect the ECG; in these cases the stress test will be normal.
An exercise stress test is considered positive for myocardial ischemia when large (>2 mm)
ST-segment depressions or hypotension (a drop of >10 mm Hg in systolic pressure) occur either alone or in combination. In general, the earlier the angina or ECG abnormalities occur, the more significant they will be. The exercise stress testing can help to do the following:
Determine the severity of IHD and the need for further intervention, i.e., severe symp- toms (hypotension) early in the test usually occur in those with triple-vessel disease
Assess the effectiveness of treatment, i.e., coronary artery disease patients who have undergone surgical intervention or are receiving medical therapy have an exercise stress test when they are medically stable and symptom-free
Determine functional capacity and identify any ECG changes or symptoms during (low level) exercise for patients who are post-MI
Exercise stress testing is contraindicated when it may place the patient at increased risk of car- diac instability, as in the following settings:
Aortic dissection
Acute myocardial infarction
Unstable angina
Severe CHF
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
134
Chapter 5 ● Cardiology
Uncontrolled sustained ventricular arrhythmias
Symptomatic supraventricular arrhythmia
Significant aortic stenosis
Hypertrophic cardiomyopathy
Severe uncontrolled hypertension
Patients who are unable to exercise or walk should be considered for chemical stress testing, such as dipyridamole (Persantine) or dobutamine stress test. Presence of baseline ECG abnormalities such as bundle branch block, left ventricular hypertrophy, or with a pacemaker, may make it more difficult to interpret test results. In those cases patients should be evaluated by nuclear stress imaging instead of the exercise stress test. These tests may also be used in patients who are taking digoxin.
In most cases, medications should not be withheld in preparation for an exercise stress test. Certain medications require special consideration:
Beta blockers may blunt the heart rate during exercise and thus should be held
24 hours prior to the test. While patients receiving beta blockers may perform the exercise required for the test, the usual age-adjusted target heart rate may not be a realistic end point for them.
• Also, the antihypertensive effect of beta blockers, alpha blockers, and nitroglycerin may cause significant hypotension during exercise.
Digoxin may depress the ST segments, so if ST-segment depression of ≥1 mm is present on baseline ECG, the stress test results will be difficult to interpret.
A number of other situations or conditions may reduce the validity of the exercise stress test. Exercise testing in asymptomatic, young women yields an increased number of false-positive results, while exercise testing in patients with known CAD may result in an unacceptably high false-negative rate (e.g., a negative stress test in a 64-year-old man with diabetes, hyperlipid- emia, and typical stable angina is likely to be a false-negative result).
The most likely cause of her abnormal stress test? False-positive test.
Other types of stress tests include:
• Nuclear stress test: A radioactive substance is injected into the patient and perfusion of heart tissue is visualized. The perfusion pictures are done both at rest and after exercise. An abnormal amount of thallium will be seen in those areas of the heart that have a decreased blood supply. Compared to regular stress tests, the nuclear stress tests have higher sensitivity and specificity (92% sensitivity, 95% specificity vs. 67% sensitivity, 70% specificity). These tests are also not affected by baseline changes in the ECG (LBBB, ST-segment depression at baseline, etc.).
• Dobutamine or adenosine stress test: Used in people who are unable to exercise. A drug is given to induce tachycardia, as if the person were exercising.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
135
USMLE Step 2 l Internal Medicine
Stress echocardiogram: Combines a treadmill stress test and an echocardiogram (ECHO). The latter can recognize abnormal movement of the walls of the left ventricle (wall motion abnormalities) that are induced by exercise.
Invasive techniques: Cardiac catheterization is also used in patients with stable angina for (1) diagnosis and (2) prognosis/risk stratification. Angiography is an appropriate diagnostic test when noninvasive tests are contraindicated or inadequate due to the patient’s illness or physical charac- teristics (e.g., morbid obesity, COPD). Cardiac angiography is also used after conventional stress tests are positive to identify patients that will benefit from stent placement or bypass surgery.
Treatment. For individual episodes of angina, nitroglycerin (NTG) sublingual tablets typically alleviate the pain within 3 minutes. Long-term management is with long-acting nitrates and/or beta blockers. Other medications patients with stable angina should be taking, unless contrain- dicated, include aspirin and statins (for lipid lowering). Also, modify the risk factors (tobacco cessation, exercise, control of hypertension, etc.).
All patients with stable angina need evaluation of the severity of IHD (cardiac angiography or stress testing, see above), and those who will benefit from revascularization (stent or bypass surgery) need to be identified.
Lipid lowering treatment for secondary prevention is important in IHD patients who should be treated aggressively. Most patients will require both pharmacologic and nonphar- macologic interventions to reach target goals. Target goals for hyperlipidemic patients with coronary artery disease include:
The optimal LDL-cholesterol goal is considered to be <70 mg/dL for patients considered to be very high risk. These are patients with established cardiovascular disease plus diabetes and patients with acute coronary syndromes. Bottom line: almost all patients with chronic stable coronary artery disease will likely need to be on statin therapy, unless contraindicated.
Every effort should be made to ensure that patients with coronary artery disease receive optimal lipid therapy. Statin medications are strongly supported as first-line medications due to compelling evidence of mortality reduction from multiple clinical trials. If patients are intolerant to a statin, consider other statins in reduced doses.
Better medical therapy with aspirin, beta blockers, ACE inhibitors, and statins are decreasing the need for all revascularization procedures.
Coronary bypass graft
Coronary artery bypass graft surgery (CABG) is recommended for patients with obstructive coronary artery disease whose survival will be improved compared to medical therapy or percutaneous coronary intervention. Typically, this means patients with left main disease or triple-vessel disease and low ejection fraction. In addition, patients with angina refractory to medical therapy qualify for CABG.
CABG is more efficacious in diabetics and in those who have a low ejection fraction. The proce- dure involves the construction of 1 or more grafts between the arterial and coronary circulations. (Many patients receive both arterial and venous grafts.) Long-term graft patency is significantly
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
136
Chapter 5 ● Cardiology
better with the arterial graph (e.g., internal mammary artery). Potential consequences of graft failure (loss of patency) include the development of angina, myocardial infarction, or cardiac death.
Percutaneous coronary intervention (PCI)
• Stent placement now standard
• Most cases of stable angina do not need PCI
• PCI is most useful in acute coronary syndrome (ACS)
Clinical Recall
Smoking cessation
All of the above
Acute coronary syndrome (ACS) describes a range of thrombotic coronary diseases, including unstable angina (UA), non-ST elevation myocardial infarction (NSTEMI), and ST-eleva- tion myocardial infarction (STEMI). Collectively, they represent one of the most common causes of acute medical admission to U.S. hospitals.
The term ACS is clinically useful because the initial presentation and early management of unstable angina, STEMI, and NSTEMI are frequently similar. ACS should be distinguished from stable angina, which develops during exertion and resolves at rest.
ACS is due to coronary vessel atherosclerotic obstruction with superimposed thrombotic occlusion. The natural course of coronary atherosclerotic plaque development and subsequent occlusion does not proceed in a step-wise, uniform manner, gradually progressing to luminal obstruction (and symptoms) over many years. This process is characterized by plaque disrup- tion and mural thrombosis. Angiographic data support the concept that noncritical lesions account for the majority of the ACS. Thus, the pathogenic rate-limiting mechanism of the ACS appears to be acute thrombosis and the resultant obstruction of the coronary lumen.
An operational classification is clinically helpful since it allows the simple distinction of the different types of ACS. In this classification, the ECG is the most important clinical tool. The initial ECG findings, in particular, the presence or absence of ST-segment elevation, will further define the patient’s condition and dictate treatment options.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
137
USMLE Step 2 l Internal Medicine
Acute Coronary Syndrome
Electrocardiogram
ST elevation (cardiac markers commonly negative on initial testing but eventually positive)
No ST elevation
Negative
Unstable angina
Figure 5-3. Acute Coronary Syndromes
UA and NSTEMI are closely related in terms of clinical presentation and pathogenesis, but patients with these conditions have widely varying risks. Both are usually caused by athero- sclerotic CAD and present an increased risk for death and MI.
NSTEMI is more severe than UA, and is considered to have occurred if ischemia produces damage detectable by biochemical markers of myocardial injury (troponin I or CK-MB).
If there are no detectable serum markers of myocardial injury 12–18 hours after symp- tom onset, the patient should be diagnosed with UA.
At the time of presentation, UA and NSTEMI may be indistinguishable and can be identically managed.
Therefore, in establishing the diagnosis of NSTEMI, cardiac troponins (elevated enzymes show evidence of infarction) should be used to distinguish this entity from UA.
Outcomes in UA/NSTEMI are generally better than in STEMI, but certain UA/NSTEMI patients are at high risk for MI or death, and it is important to identify these patients at initial screening because they may require intensive monitoring and management.
Thrombolytic therapy is beneficial in patients with STEMI, but is not effective in UA or NSTEMI and may be harmful.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
138
Chapter 5 ● Cardiology
Unstable angina is sometimes referred to as “crescendo” or “preinfarction” angina. Typically, it is defined as angina of increasing severity, frequency, duration; angina showing increasing resistance to nitrates; or angina occurring at rest. Experts also regard any new-onset angina as unstable. Sudden change in the pattern of angina usually means a physical change within the coronary arteries, such as hemorrhage into an atherosclerotic plaque or rupture of a plaque with intermittent thrombus formation.
About 35% of patients with the clinical syndrome of UA will already have coronary thrombosis on catheterization. In fact, untreated UA progresses to MI in 50% of cases, thus the patient with new-onset or unstable angina should be hospitalized for intensive medical treatment.
Most patients with NSTEMI have a normal physical examination. An abnormal ECG, particularly dynamic ST-segment deviation (≥0.5 mm), or new T-wave inversion (≥2 mm), will confirm the diagnosis, but the ECG may be normal or show minor changes in up to 50% of cases.
High-risk features for patients with presumed UA/NSTEMI include:
• Repetitive or prolonged chest pain (>10 min)
• Persistent ECG changes of ST depression >0.5 mm or new T-wave inversion
• Hemodynamic instability (SBP <90)
• Sustained ventricular tachycardia
• Syncope
• Prior angioplasty or prior CABG
• Diabetes
General management
Aspirin is recommended (unless contraindicated) in all patients. High-risk patients should be treated with aggressive medical management and arrangements should be made for coronary angiography and possible revascularization, except in those with severe comorbidities. Age alone should not be a barrier to aggressive therapy.
Medical management
Antiplatelet therapy (beyond aspirin): Early treatment should be initiated with aspirin and clopidogrel or prasugrel, with the following considerations:
• Avoid clopidogrel in patients likely to require emergency coronary bypass surgery. Prasugrel and ticagrelor are alternatives to clopidogrel.
• If possible, discontinue clopidogrel 5 days before coronary bypass surgery.
• Use ticagrelor in addition to aspirin for acute coronary syndromes. It is not clearly better than clopidogrel or prasugrel.
• Give heparin along with the recommended antiplatelet therapy for UA/NSTEMI.
Antithrombin therapy: Give unfractionated heparin or subcutaneous enoxaparin until angiography or for 48–72 hours. The enoxaparin dose must be reduced in patients with impaired renal function.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
139
USMLE Step 2 l Internal Medicine
Note
The strongest indication for PCI is an acute coronary syndrome.
Glycoprotein (GP) IIb/IIIa inhibitors: This class of antithrombotic agents inhibits platelet function by blocking a key receptor involved in platelet aggregation. The use of these agents provides a more comprehensive platelet blockade than the combination of aspirin and heparin.
These drugs take advantage of the fact that platelets play an important role in the development of ischemic complications that may occur in patients with UA/NSTEMI.
Tirofiban or eptifibatide is particularly recommended in high-risk patients in whom an invasive strategy is planned.
Concomitant tirofiban is particularly beneficial and recommended in patients with diabetes.
Complications include bleeding and thrombocytopenia (occurs with all GP IIb/IIa agents; incidence ranges 1–5.5% in clinical studies; an immune mechanism is likely responsible; all patients receiving parenteral GP IIb/IIa antagonists should be moni- tored for 24 hours for development of thrombocytopenia).
Other: A beta blocker should be given unless contraindicated. IV nitroglycerin (NTG) can be given for refractory pain.
In patients with diabetes, good glycemic control should be targeted in the hospital and after discharge. This may require considering an insulin-based regimen in hospital.
Early coronary angiography (within 48 hours) and revascularization are recommended in patients with NSTEMI and high-risk features, except in patients with severe comorbidities. Pain or ischemia refractory to medical therapy and high-risk features on early exercise testing can also identify patients suitable for early invasive therapy.
Which of the following medications must be withheld before performing an exercise stress test?
Metoprolol
Nimodipine
Aspirin
Lisinopril
Answer: B
ST Elevation MI
The pain of typical MI (STEMI; in the past referred to as Q wave MI) is substernal, diffuse with a pressure quality. It may radiate to the neck or jaw, shoulders, or arms. Often, the pain is accompanied by additional symptoms, such as dizziness (lightheadedness), nausea or vomiting, diaphoresis, or shortness of breath (dyspnea).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
140
Chapter 5 ● Cardiology
The symptoms of MI last >20 minutes and do not respond completely to nitroglycerin. The duration of the pain is variable. Pain may resolve completely after a few hours or may persist for over a day.
Elderly or diabetic patients are prone to atypical symptoms such as nausea or dyspnea as the sole symptoms of infarction. As many as 20% of MI are “silent”—that is, whatever symptoms were present did not impress the patient enough for them to seek medical care or even to remember the incident.
• The exam usually shows the patient to have anxiety and pain.
• Diaphoresis is often present.
• Pulse rate may be normal, but often bradycardia is present in inferior infarctions. Tachycardia is often seen with large infarctions.
• Blood pressure is often elevated.
• Cardiac exam is usually normal.
• Large infarctions may cause signs of ventricular failure or valve dysfunction. A fourth heart sound (S4) is common due to a stiffened ventricle. Mitral regurgitation may occur if papillary muscles malfunction. The second heart sound may be paradoxically split as the left ventricular contraction time increases due to LBBB and weakened left ventricle.
Later in the course of MI, other findings may be present: mild fever, pericardial friction rub, ventral septal defect murmur due to septal rupture, or severe mitral regurgitation due to papillary muscle rupture.
STEMI is defined as clinical symptoms consistent with ACS and ECG features including any of these:
• Persistent ST-segment elevation of ≥1 mm in 2 contiguous limb leads
• ST-segment elevation of ≥2 mm in 2 contiguous chest leads
• New LBBB pattern
Initially, you don’t need increased cardiac biomarkers (troponin, CPK-MB, etc.) to make the diagnosis of STEMI (although these are usually eventually positive at some point during the course of the disease).
Initial nonspecific management for all patients with possible MI (anyone with a compatible chest pain history) is to keep them on a cardiac monitor. Oxygen therapy and an IV line should be established as quickly as possible. Aspirin should be given unless contraindicated, as early as possible. Nitroglycerin and pain control (morphine) should be given as required.
Patients with STEMI usually have a completely occluded coronary artery with thrombus at the site of a ruptured plaque. This eventually leads to myonecrosis. Restoring coronary patency (emergency reperfusion) as promptly as possible is a key determinant of short-term and
long-term outcomes.
Patients with STEMI who present within 12 hours of the onset of ischemic symptoms should have a reperfusion strategy implemented promptly. Reperfusion may be obtained with fibrinolytic therapy or percutaneous coronary intervention (PCI).
Patients presenting with NSTEMI will not benefit from thrombolytics.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
141
USMLE Step 2 l Internal Medicine
I | a | V | R | V | 1 | V4 | |||||||||||||||||||||||
II | a | VL | V | 2 | V5 | ||||||||||||||||||||||||
II | I | a | V | F | V | 2 | V6 | ||||||||||||||||||||||
II | |||||||||||||||||||||||||||||
V | I | ||||||||||||||||||||||||||||
V | 5 |
Figure 5-4. Anteroseptal STEMI with Changes in V1–V3
V
Figure 5-5. Inferior STEMI with Changes in II, III, and aVF
I
a
V
R
V
1
V4
II
a
VL
2
V5
III
a
VF
2
V6
V1
II
V
V5
Figure 5-6. NSTEMI Affecting Leads II, III, and aVF
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
142
Chapter 5 ● Cardiology
Table 5-2. Localization of STEMI
Area of Infarction | EKG Changes (Q Waves, ST Elevation, T Wave Inversions) | Artery Involved |
Inferior | II, III, aVF | Right coronary |
Anteroseptal | V1–V3 | Left anterior descending |
Anterior | V2–V4 | Left anterior descending |
Lateral | I, aVL, V4, V5, and V6 | Left anterior descending or circumflex |
Posterior | Posterior descending |
Table 5-3. Typical Electrocardiographic Evolution of a STEMI
EKG Abnormality | ||
Hyperacute T waves (tall, peaked T waves in leads facing infarction) | ||
ST-segment elevation | ||
Q waves longer than 0.04 seconds | ||
T wave inversion |
The choice of reperfusion therapy is between PCI and thrombolysis therapy. PCI is the best available treatment if provided promptly. PCI improves short-term and long-term outcomes (reduction of deaths and MI) in patients with STEMI presenting within 12 hours when compared with thrombolytic therapy. This benefit over thrombolysis may occur only if the additional time delay associated with PCI is <1 hour. In general, a time delay of 90 minutes from first medical encounter to PCI is the maximum desirable. For patients presenting with STEMI at a facility without PCI access, transfer to another facility capable of performing PCI usually takes too long. Where PCI is delayed or not available, reperfusion with thrombolytic therapy should occur unless contraindicated.
Thrombolytics (Fibrinolytics)
Thrombolytics such as streptokinase or tissue-type plasminogen activator (tPA) restore perfu- sion to the ischemic area by lysing the clot, thereby reducing infarct size and improving survival.
Thrombolysis benefits patients with all types of ST elevation infarction, but the benefit is several times greater in those with anterior infarction. The earlier the treatment is given, the greater the absolute benefit. The greatest benefit is in patients with ST elevation or new left bundle branch block who have had symptoms for <12 hours.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
143
USMLE Step 2 l Internal Medicine
Streptokinase and alteplase are given by IV infusion. Reteplase and tenecteplase can be given by rapid bolus injection. tPA is the most common agent used in the U.S. Prolonged persis- tence of antibodies to streptokinase may reduce the effectiveness of subsequent treatment; therefore, streptokinase should not be used if used within the previous 12 months in the same patient. Complexity of administration differs among the different thrombolytics: tenecteplase and reteplase are ready in about 1 minute; for streptokinase or tPA, the typical time from physician order to administration is 12 to 15 minutes.
Bottom line: consider a thrombolytic agent as an alternative to primary PCI in suitable candi- dates with:
ST-elevation MI (>1 mm ST elevation in 2 contiguous leads)
New LBBB
Contraindications to thrombolytic therapy:
Late presentation (>12 hours after symptom onset): Reperfusion therapy with either PCI or fibrinolysis is not routinely recommended in patients who are asymptomatic and hemodynam- ically stable, and who present >12 hours after symptom onset.
Other interventions may include coronary artery bypass grafting (CABG). CABG surgery may occasionally be more appropriate—particularly in patients who have suitable anatomy and are not candidates for fibrinolysis or PCI. CABG surgery may also be considered in patients with cardiogenic shock or in association with mechanical repair.
Adjuvant therapy used together with reperfusion
Antiplatelet Therapy
Aspirin should be given to all patients with presumed STEMI unless contraindicated, and, in the absence of significant side effects, low-dose therapy should be continued in the long term.
Clopidogrel or prasugrel should be prescribed in addition to aspirin for patients undergoing PCI with a stent. Ticagrelor is an alternative to clopidogrel or prasugrel.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
144
Chapter 5 ● Cardiology
In patients selected for fibrinolytic therapy, clopidogrel should be given in addition to aspirin, unless contraindicated. Note, however, that if it is thought that the patient is likely to require CABG acutely, clopidogrel should be withheld.
Clopidogrel should be continued for at least a month after fibrinolytic therapy, or for up to 9–12 months after stent implantation, depending on the type of stent used.
Antithrombin Therapy
With PCI: Antithrombin therapy should be used in conjunction with PCI. The dose of unfractionated heparin therapy will depend on concomitant use of glycoprotein (GP) IIb/IIIa inhibitors. It may be advisable to give a bolus of heparin while the patient is in transit to the catheterization laboratory.
The role of enoxaparin in acute STEMI in conjunction with PCI remains to be fully determined, but it appears to be safe and effective.
With fibrinolysis: Antithrombin therapy should be used with fibrin-specific fibrinolytic agents.
IV unfractionated heparin should be given as an initial bolus, adjusted to attain the activated partial thromboplastin time (APTT) at 1.5 to 2 times control. IV unfractionated heparin is used when rapid reversal is needed. The half-life is shorter with unfractionated heparin.
Glycoprotein IIb/IIIa Inhibitors
It is reasonable to use abciximab with primary PCI. Eptifibatide and tirofiban are the other GPIIb/IIIa inhibitors. Full-dose GP IIb/IIIa inhibitors should be avoided with fibrinolytic therapy as there is evidence of excessive bleeding (including intracranial hemorrhage) with this combination.
The combination of GP IIb/IIIa inhibitors with reduced doses of fibrinolytic therapy is not recommended. There is no significant advantage over full-dose fibrinolytic therapy alone, and the risk of bleeding is increased, particularly in the elderly.
Cardiac surgery
Emergency bypass surgery should be considered in patients with STEMI and: (1) failed PCI with persistent pain or hemodynamic instability and coronary anatomy suitable for surgery or (2) persistent or recurrent ischemia refractory to medical therapy and suitable anatomy.
Recommended discharge medications after ACS
Aspirin: All patients should take daily unless contraindicated.
Clopidogrel: There is evidence that clopidogrel or prasugrel should be prescribed for up to 9–12 months after acute myocardial infarction, particularly after stent placement. Clopidogrel may also be prescribed as an alternative when aspirin is contraindicated, or to those intolerant to aspirin, in patients with recurrent cardiac events.
Beta-blocker: These drugs should be prescribed for all patients after an ACS unless contraindicated, and continued indefinitely. Metoprolol and carvedilol particularly should be used in patients after ACS who have heart failure.
Note
To remember issues that need to be considered at the time of discharge, remember “ABCDE” (aspirin and anti- anginals, beta blockers and blood pressure, cholesterol and cigarettes, diet and diabetes, education and exercise).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
145
USMLE Step 2 l Internal Medicine
ACE inhibitors: Should be given in patients with ACS in CHF, left ventricular dysfunction (ejection fraction <40%). Its use should be reviewed later on the course of the patient and discontinued if the heart failure resolves.
Statins: Statin therapy should be initiated in the hospital in all patients with ACS (the exception is the rare ACS that is not related to atherosclerosis).
Nitrates: Long-acting nitrates (isosorbide) should be reserved for the patients with persistent chest pain.
Warfarin: It is recommended after ACS only for those at high risk of systemic throm- boembolism because of atrial fibrillation or mural thrombus.
Secondary prevention through the control or elimination of known risk factors for coronary artery disease (e.g., hyperglycemia in patients with diabetes mellitus, HTN control, tobacco cessation, physical inactivity) also should be part of discharge planning.
You are asked by your patient, who has a history of ischemic heart disease, about drug treatments that have been shown to decrease mortality in his case. (It doesn’t matter if he has stable angina or prior history of acute coronary syndrome.)
Answer: Lipid lowering agents (statins), ASA, Beta-blocking agents and CABG in patients with triple vessel disease or left main disease.
Exercise ECG testing: Increasingly, submaximal testing is performed 4–7 days after infarction. A maximal test can be performed at 3–6 weeks postinfarction. It is used to assess prognosis and to identify those patients with reversible ischemia who should then have an angiogram (if one has not been done) to assess the need for coronary artery bypass graft.
Myocardial perfusion imaging can be performed before hospital discharge to assess the extent of residual ischemia if the patient has not already undergone cardiac catheterization and angiography.
Electrical disturbances dysrhythmias
Bradycardia: sinus, atrioventricular junctional, idioventricular. These are treated acutely with atropine and temporary pacing if severe.
Premature beats: atrial, ventricular. No treatment is needed for ectopy such as these.
Tachyarrhythmias (supraventricular): atrial tachycardia, atrial fibrillation, atrial flutter, AV junctional; are seldom caused by ischemia
Tachyarrhythmias (ventricular): ventricular tachycardia, accelerated idioventricular rhythm, ventricular fibrillation
Conduction Abnormalities
Atrioventricular nodal: first-, second-, and third-degree block
Intraventricular: hemiblocks (left anterior, left posterior), bundle branch block, third-degree atrioventricular block
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
146
Chapter 5 ● Cardiology
Pump dysfunction
• Contractile dysfunction: left ventricular, right ventricular, and biventricular failure; true ventricular aneurysm; infarct expansion
• Mechanical disruption: acute mitral regurgitation (papillary muscle dysfunction or rupture), ventricular septal rupture, free wall rupture, pseudoaneurysm; treated with emergency surgical repair
• Electromechanical dissociation
Ischemia
• Postinfarction ischemia: ischemia in the infarct and ischemia distant to the infarct
• Early recurrent infarction or infarct extension
• Postinfarction angina after thrombolytics or PCI should be treated with bypass surgery
Pericarditis—Dressler syndrome (late)
Treated with aspirin, NSAIDs, and later steroids if there is no response.
Thromboembolic
• Mural thrombus with systemic embolism
• Deep vein thrombosis with prolonged immobilization
Sudden cardiac death
• Ventricular fibrillation (most commonly)
Right ventricular infarction
Accompanies 30% of inferior MIs. It is diagnosed with RV leads and treated with fluids.
Non-Cardiac Complications of ACS
Depression is 3x more common in those who have had a heart attack than in the general population, with 20% of heart attack victims qualifying for a diagnosis of major depressive disorder, and a far greater proportion experiencing increased levels of depressive symptoms. Beyond the accompanying emotional distress and suffering, depression also increases one’s risk of having another heart attack or dying over the ensuing months and years.
There is reliable evidence that both antidepressant medications and certain forms of psycho- therapy are effective in reducing depression in the post-MI state. Selective serotonin reuptake inhibitors (SSRIs) such as sertraline and citalopram have been found to be both effective in reducing depression and relatively safe for use in patients with coronary heart disease. Cognitive behavior therapy has also been found to be effective in treating depression.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
147
USMLE Step 2 l Internal Medicine
Erectile dysfunction (ED) is prevalent among patients with CAD and post-MI (in some series ~ 40%).
ED complicates the recovery of those post-MI.
Treatment of post-MI patients includes management of depression, reassurance, and modification of medications that may cause ED.
Sildenafil should be used cautiously in men post-MI who are taking nitrates of up to 55 mm Hg, because it can cause a drop in BP. Due to this synergistic effect, it is therefore contraindicated in patients taking nitrates.
ED is a complication of the conditions that are primary risk factors for developing CAD, in particular, diabetes, hypertension, dyslipidemias, and arteriosclerosis.
Smoking and stress are implicated in the development of ED.
In evaluating risk of MI associated with intercourse in patients with cardiac disease, it has been estimated that <1% of MIs occur during sexual activity. Although sexual activity can trigger MI, the relative risk is low with a slight increase in risk within 2 hours of sexual activity.
However, even in high-risk individuals with previous MI the annual risk is 1.10% vs. 1.0% in the population at large. This risk appears to apply equally to men and women.
Patients can therefore be risk-stratified and counseled about safely returning to or continuing sexual activity:
Low risk: asymptomatic patients with fewer than 3 risk factors for CAD, stable angina, recent uncomplicated MI, mild valvular heart disease, mild CHF, controlled hypertension, or post successful revascularization; patients can generally be managed medically and followed at regular intervals
Intermediate risk: those with recent MI (but beyond 2 weeks), moderate CHF (New York Heart Association class II) and those with >3 risk factors for CAD; patients may benefit from functional testing, i.e., exercise treadmill tests (ETT), echocardiography, or nuclear imaging study with re-stratification based on results of testing
ETT can assist in gauging cardiac risk of sexual activity, both for induction of ischemia or arrhythmia. In general, if a patient can achieve 5 METs on ETT without demonstrable ischemia or significant arrhythmia, he is not at high risk to resume normal sexual activities
Similarly, if echocardiography does not yield evidence of more than moderate left ventricular dysfunction, resumption of sexual activity is probably safe
High-risk: those with unstable angina, MI within 2 weeks, poorly controlled hypertension, severe CHF (New York Heart Association class III/IV), significant arrhythmias, severe cardiomyopathies; patients should be referred for cardiovascular evaluation and stabilization prior to recommending resumption of sexual activity.
Nonatherosclerotic Acute Coronary Syndromes
Although thrombotic complications of the atherosclerotic process account for most cases of acute coronary syndromes, there are a few rare etiologic factors that have been proposed as causes of or contributors to acute coronary occlusion. These causes include coronary artery spasm, spontaneous coronary dissection, coronary artery embolization, coronary arteritis, and hypercoagulability states such as factor V gene mutation, deficiencies of proteins C and S, antithrombin III deficiency, antiphospholipid antibody syndrome, and prothrombin gene
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
148
Chapter 5 ● Cardiology
mutation. Cocaine use has been documented to induce coronary vasoconstriction in nondis- eased coronary segments but is more pronounced in atherosclerotic segments.
Prinzmetal angina, or variant angina, is a very uncommon condition in which episodes of severe angina are triggered when one of the major coronary arteries suddenly goes into spasm. These episodes are accompanied by ST-segment elevation on the ECG. Although the spasm almost always terminates spontaneously, Prinzmetal angina may be associated with acute MI, serious ventricular arrhythmias, and sudden death.
As opposed to typical angina, Prinzmetal angina usually occurs during periods of rest, most often at night and in the early morning hours. Frequently, episodes appear in clusters. In men, Prinzmetal angina is often associated with atherosclerosis; in women it is not. Women with Prinzmetal tend to have few risk factors for CAD, though many have a history of migraine headaches (another condition associated with arterial spasm).
Exercise testing and routine coronary angiography usually give normal results. Ergonovine has been used to trigger coronary artery spasm in susceptible patients, confirming the diagnosis. Treatment with calcium channel blockers or nitrates eliminates spasm in most of these patients. Once adequately treated, their prognosis is good.
During an acute episode of pain and ST segment elevation, you cannot tell who has Prinzmetal variant angina and who has an acute ST elevation MI. Therefore, you must initially treat everyone with chest pain and ST elevation as if they were having an acute MI. Prinzmetal angina can be confirmed only after coronary angiography.
Causes of MI without Coronary Atherosclerosis
Vasculitis
Polyarteritis nodosa
Takayasu arteritis
Coronary spasm
Variant angina
Cocaine abuse
Coronary artery embolus
Atrial myxoma
Atrial or ventricular thrombus
Hypercoagulable states
Polycythemia vera
Thrombocytosis
Factor V Leiden
Protein C deficiency
Antiphospholipid antibodies
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
149
USMLE Step 2 l Internal Medicine
Clinical Recall
Which of the following is not an absolute contraindication to thrombolytic therapy?
Active bleeding from factor VIII deficiency
Epidural hematoma within the last 3 months
Cholecystectomy 3 weeks ago
Prior basal ganglia hemorrhage
Large MCA stroke within the last 3 months
Answer: C
CONGESTIVE HEART FAILURE (CHF)
Heart failure (HF) arises from the inability of the ventricle to efficiently pump blood through- out the circulation. Clinically HF presents with symptoms of breathlessness, exercise intoler- ance, and fatigue.
A 57-year-old man with history of multiple myeloma presents with dyspnea and lower-extremity edema for 2 months. On exam there is jugular venous distention (about 8 cm.), an audible S4, and the apical impulse is non-displaced at the 5th intercostal space. The chest x-ray shows normal cardiac silhouette. The echocardiogram shows a thickened left ventricle with an ejection fraction of 65%.
As HF evolves, changes in vascular function, blood volume, and neurohumoral status occur throughout the body. These changes serve as compensatory mechanisms to help maintain car- diac output (primarily by the Frank-Starling mechanism) and arterial blood pressure (by sys- temic vasoconstriction). However, these compensatory changes over time can worsen cardiac function. Cardiac changes during HF include increased end-diastolic volume; ventricular dila- tation or hypertrophy; decreased stroke volume and cardiac output; reduced ejection fraction
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
150
Chapter 5 ● Cardiology
(systolic dysfunction) or impaired filling (diastolic dysfunction). Compensatory mechanisms during HF include:
• Cardiac: Frank-Starling mechanism, tachycardia, ventricular dilatation
• Neuronal: increased sympathetic adrenergic activity, reduced cardiac vagal activity
• Hormonal: activation of angiotensin-aldosterone system, vasopressin, catecholamines, and natriuretic peptides
In clinical practice, HF is commonly categorized by whether the abnormality is due to contrac- tion or relaxation of the heart. Systolic HF (systolic dysfunction) is due to a loss of contractile strength of the myocardium accompanied by ventricular dilatation. This type of HF is also accompanied by a decrease in normal ventricular emptying (usually ejection fraction <45%). Examples of systolic HF include ischemic cardiomyopathy and dilated cardiomyopathy (Case 1 in this section).
Heart failure with preserved ejection fraction (diastolic dysfunction) occurs when the filling of one or both ventricles is impaired while the emptying capacity is normal (echocardiogram confirms that the ejection fraction is normal). The infiltrative cardiomyopathies (amyloidosis) are typical examples (Case 2 in this section).
Peripheral edema
i systemic vascular resistance
Reflex arteriolar vasoconstriction
i afterload
(LV impedance)
i blood volume
NaCl and H20 retention
i renin
i angiotensin II i aldosterone i vasopressin
Figure 5-7. Inter-related Cycles in Congestive Heart Failure
Congestive HF indicates a clinical syndrome of dyspnea and fatigue as well as evidence of features of circulatory congestion (peripheral edema, elevated jugular venous pressure [JVP]). In heart failure, intravascular congestion occurs with elevation of left ventricular diastolic and pulmonary venous pressures that eventually causes transudation of fluid from the pulmonary capillaries into the interstitial space. Pulmonary edema develops when the rate of fluid accumulation goes above the rate of lymphatic absorption. Pulmonary edema is detected by audible crackles, increased JVP and edema on exam, and chest x-ray findings.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
151
USMLE Step 2 l Internal Medicine
Clinical Pearl
In the work-up of patients with new-onset HF, always try to identify potentially reversible causes.
Decompensated HF or exacerbation of HF denotes worsening of symptoms and clinical findings in pre-existing HF. This can be due to precipitating factors such as non-adherence to medication, increase in dietary salt, acute ischemia, tachycardia, or pulmonary infection.
In evaluating patients with HF or worsening of pre-existing HF, it is also important to exclude precipitating factors. Commonly, HF manifests for the first time when a precipitating factor places additional burden on the heart. Such factors include:
Uncontrolled hypertension (especially after abrupt cessation of anti-hypertensive medication)
Thyrotoxicosis
Anemia
HF may occur as a consequence of most causes of heart disease, but ischemic heart disease is responsible for over 70% of all cases in the western world. Other common causes include: hypertensive heart disease, the cardiomyopathies (idiopathic, alcohol related, etc.), and valvular and congenital heart diseases.
Symptoms of HF include dyspnea (differentiate from pulmonary dyspnea), orthopnea, paroxysmal nocturnal dyspnea, and fatigue/weakness.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
152
Chapter 5 ● Cardiology
Physical findings in HF:
• Pulmonary rales
Table 5-4. Most Common Causes of Acute Pulmonary Edema
Ischemia |
Arrhythmia |
Non-adherence with medication |
Dietary indiscretion |
Infection |
Clinical Pearl
In the work-up of patients with exacerbation of HF, always:
• Check cardiac enzymes to exclude myocardial ischemia or infarction
• Do a chest x-ray to exclude infection
• Hepatomegaly
• Displaced apical impulse (systolic HF)
Wikipedia, James Heilman, MD
Figure 5-9. Pitting Edema
The severity of heart failure is commonly classified by using a HF staging system. The New York Heart Association Functional Classification (NYHA staging system) relates symptoms to everyday activities and the patient’s quality of life:
• Class I: patients have no limitation of activity; they suffer no symptoms from ordinary activities
• Class II: patients with slight, mild limitation of activity; they are comfortable with rest or with mild exertion
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
153
USMLE Step 2 l Internal Medicine
Clinical Pearl
The single best test for the evaluation and diagnosis of heart failure is the echocardiogram.
Note
BNP is used acutely if the cause of dyspnea is not clear.
Class III: patients with marked limitation of activity; they are comfortable only at rest
Class IV: patients are confined to bed or chair; any physical activity brings on discomfort and symptoms occur at rest
Copyright 2007 Gold Standard Multimedia Inc.
Figure 5-10. Chest X-ray Demonstrating Acute Exacerbation of Congestive Heart Failure
Diagnosis. Echocardiography is the test-of-choice to confirm the diagnosis of HF and to classify the type (systolic vs. diastolic). With the echocardiogram, the clinician is able to determine ejection fraction and identify valvular heart disease as well as other cardiac anoma- lies (dilated ventricle, thickened ventricle, etc.).
Chest x-rays are also used to aid in the diagnosis of heart failure. They may show cardiomegaly, vascular redistribution, Kerley B-lines, and interstitial edema.
Electrocardiogram is used to identify ventricular hypertrophy and/or the presence of isch- emic heart disease, arrhythmias, or conduction delays which may cause or precipitate HF.
Brain Natriuretic Peptide (BNP) is a polypeptide secreted by the heart in response to excessive stretching of the myocytes. It is a valuable tool in the evaluation of patients with presumed HF or decompensated HF in the acute setting. The BNP is almost always elevated (97% sensitivity) in patients with decompensated HF. Normal BNP excludes CHF as the cause of dyspnea.
Management. The treatment goals in HF are to improve hemodynamics, relieve symptoms (improve quality of life), and prolong survival. Remember, always evaluate for reversible causes at the same time.
Non-pharmacologic treatment includes primarily reduction of salt intake.
For pharmacologic treatment, ACE inhibitors are the basis of therapy and recommended for all patients with HF (especially systolic HF), irrespective of blood pressure status. They improve survival and reduce ventricular hypertrophy—and eventually, symptoms. ACE inhibitors through vasodilation reduce preload and afterload, thereby reducing right atrial, pulmonary
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
154
Chapter 5 ● Cardiology
arterial, and pulmonary capillary wedge pressures. All ACE inhibitors have been studied and are considered equal in terms of HF treatment. Angiotensin receptor blockers (ARB) are acceptable alternatives if the patient is unable to tolerate ACE inhibitors (cough, angioedema).
Diuretic therapy, especially loop diuretics, is the treatment of choice for the relief of acute pulmonary edema symptoms. Several classes are used but the loop diuretics (furosemide) class is the most commonly used. Thiazide diuretics (hydrochlorothiazide) are useful only in mild HF. Spironolactone and eplerenone (aldosterone antagonists) have been used as add-on therapy to ACE inhibitors in severe heart failure to prolong survival by presumed aldosterone inhibition.
Table 5-5. Vasodilators Used in Congestive Heart Failure
Drug | Site of Action | Route of Administration | Complications |
Captopril Enalapril Lisinopril | Arteriolar and venous ACE inhibitor | ||
Nitroprusside | Arteriolar and venous | ||
Nitroglycerin | |||
Isosorbide dinitrate | Venous | ||
Hydralazine | Positive ANA, SLE-like syndrome (10–20% if >400 mg/d) drug fever, rash |
Chronic adrenergic activation has been implicated in the pathogenesis of HF and thus β-adrenergic blocking agents are an important part of HF therapy. Along with ACE
inhibitors, beta blockers have been demonstrated to decrease mortality, reduce hospitaliza- tions, improve functional class, and improve ejection fraction in several large-scale, randomized, placebo-controlled trials.
Start patients on beta blockers after stabilization of symptoms with diuretic and ACE inhibitor therapy, irrespective of blood pressure status. Beta blockers such as carvedilol, metoprolol, and bisoprolol have demonstrated survival benefits in trials.
Note
ACE inhibitor (any) and a diuretic are considered first line for all patients with HF. Once the patient is stable, add carvedilol or metoprolol. Don’t
substitute β-blockers in HF since not all β-blockers have the same efficacy.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
155
USMLE Step 2 l Internal Medicine
Note
Agents which lower mortality in systolic dysfunction
ACE (ARB)
Beta blockers
Spironolactone (or
eplerenone)
Table 5-6. Commonly Used Diuretics in Heart Failure
Drug | Site of Action | Complications |
Thiazides (inhibits NaCl cotransport); used mostly for treatment of hypertension | Distal tubule | Hyponatremia, hypokalemia, hypercalcemia, metabolic alkalosis, hyperuricemia, allergy, agranulocytosis, leukopenia, pancreatitis, glucose intolerance |
Indapamide | Distal tube (direct vasodilator) | As above, but hypokalemia and lipid abnormalities less common |
Loop diuretics (inhibitors Na/K, 2Cl cotransport); most commonly used diuretics in heart failure | Loop of Henle | Hyponatremia, hypokalemia, hypocalcemia, metabolic alkalosis, hyperuricemia, interstitial nephritis, ototoxicity, thrombocytopenia, agranulocytosis, leukopenia |
Hyperkalemia, gynecomastia (spironolactone only) |
Hydrochlorothiazide
Chlorothiazide
Other vasodilators, such as a combination of hydralazine and isosorbide, may be used when ACE inhibitors and ARBs are not tolerated or contraindicated (renal failure). There is a reduction in death and a decrease in hospitalization when a combination of hydralazine and isosorbide is used.
In severe HF and especially if there is no improvement of symptoms while the patient is on standard therapy (diuretic, ACE inhibitor, and beta blocker), the addition of spironolactone may be of benefit. The addition of spironolactone in patients with severe CHF significantly reduces (about 30% relative risk) death and hospitalizations among treated patients. Spironolactone is used in patients with NYHA class III-IV. Once the patient is started on spironolactone, serum potassium levels have to be monitored closely.
Eplerenone is an alternative to spironolactone that does not cause gynecomastia.
The addition of inotropic agents to patients with severe HF improves symptoms and quality of life and reduces hospitalizations but does not improve survival. The most commonly used inotropic agent is digitalis. Digitalis inhibits Na+/K+ - ATPase pump which results in increased intracellu- lar concentration of Na+ and decreased exchanges of intracellular Ca2+. The end result is an increase in intracellular concentration of Ca2+ which results in improved cardiac contractility.
Cardiac glycosides work by inhibition of Na+/K+-ATPase pump, which results in:
Increased intracellular concentration of Na+
Decreased exchange of intracellular Ca2+ for extracellular Na+
The end result is an increase in the intracellular concentration of Ca2+, which gives the (+) inotropic effect characteristic of glycosides
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
156
Chapter 5 ● Cardiology
Remember that K+ and digitalis compete for myocardium binding sites. Hyperkalemia will decrease digitalis activity, whereas hypokalemia results in toxicity.
Digitalis will increase both the force and the velocity of the myocardial contraction. It will also promote a more complete emptying of the ventricles.
It is used for the treatment of:
• CHF
• Atrial fibrillation/flutter
• Paroxysmal atrial tachycardia/SVT
Conditions which predispose to digitalis toxicity are:
• Renal insufficiency
• Electrolyte disturbances (hypokalemia, hypercalcemia, hypomagnesemia)
• Advanced age
• Sinoatrial and atrioventricular block
• Thyroid disease, especially hypothyroidism
Table 5-7. Drug Interactions Associated with Digoxin
Drug | ||
Quinidine | ||
Verapamil, diltiazem | ||
Binds digoxin in GI tract; interferes with enterohepatic circulation | ||
Spironolactone | ||
Thiazides, furosemide | Diuretic-induced hypokalemia and/or bumetanide hypomagnesemia potentiates digitalis action |
*Increase enhances digitalis effect; decrease diminishes digitalis effect.
Note
Agents which improve heart failure symptoms but do not reduce mortality
Digoxin
Diuretics
Toxic Effects of Digitalis
Nausea and vomiting
Gynecomastia
Blurred vision
Yellow halo around objects
Arrhythmias—commonly paroxysmal atrial tachycardia (PAT) with block, PVCs (premature ventricular contractions), and bradycardia
Treatment for Intoxication
Stop drug
Lidocaine and phenytoin (for arrhythmia)
Digibind only for acute overdose
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
157
USMLE Step 2 l Internal Medicine
Clinical Pearl
Diastolic HF may worsen when diuretics and vasodilators are used excessively. The goal in diastolic HF is to slow the heart rate with beta blockers and calcium channel blockers (verapamil, diltiazem) in order to allow adequate diastolic filling.
Sympathomimetic amines (dopamine, dobutamine) and phosphodiesterase inhibitors (amri- none, milrinone) are sometimes used in the management of severe acute HF (hospitalized patients). They must be administered by IV infusion and need continuous monitoring of the blood pressure and cardiac rhythm.
Monitoring of patients with HF includes calculation of fluid intake and excretion (in the hospi- tal) as well as monitoring body weight (in the out-patient setting).
In refractory HF (defined as progression of HF despite standard treatment), the patient may be considered for: biventricular pacing, implantable defibrillator, and heart transplantation.
Medical Devices for Systolic Dysfunction
The automatic implantable cardioverter/defibrillator (AICD) is a standard therapy for ischemic dilated cardiomyopathy. Since the most common cause of death in CHF is an arrhythmia, it is logical that a device which interrupts arrhythmia will lower mortality. A biventricular pace- maker will “resynchronize” the heart when there is dilated cardiomyopathy and QRS >120 mSec. When there is a wide QRS, the 2 ventricles do not beat or depolarize in synchrony.
When you put a biventricular pacemaker into the heart, this will “resynchronize” the 2 ventricles, resulting in an immediate decrease in symptoms.
Dilated cardiomyopathy with a persistent ejection fraction <35%
Dilated cardiomyopathy with a QRS wider than 120 mSec
Biventricular pacemaker (if QRS >120 mSec)
ACE inhibitors are a class effect; there is no difference in efficacy between the drugs. There is no benefit to adding an ARB to an ACE inhibitor. With beta blockers, not all the drugs are equal; those that benefit mortality in CHF are metoprolol, carvedilol, and bisoprolol. Biven- tricular pacemakers and cardiac resynchronization therapy also have implantable defibrillator function.
Pulmonary Edema
Pulmonary edema is considered a medical emergency and requires hospitalization. It leads to impaired gas exchange and may cause respiratory failure. There are non-cardiogenic causes of pulmonary edema but in this section we will discuss only cardiogenic pulmonary edema.
Cardiogenic pulmonary edema is caused by an acute increase in left ventricular pressure due to ventricular dysfunction which leads to fluid accumulation in the pulmonary interstitium.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
158
Chapter 5 ● Cardiology
Signs and Symptoms
• Increased respiratory rate
• Cough with expectoration (pink frothy sputum)
• Cyanosis
• Nocturnal dyspnea
• Rales, rhonchi, wheezing
Chest X-ray Findings
• Prominent pulmonary vessels
• Effusions
• Enlarged cardiac silhouette
• Kerley B lines
EKG is used to determine if an arrhythmia is contributing to the development of the pulmonary edema.
Treatment
• Oxygen
• Diuretic therapy (furosemide) reduces preload
• Morphine sulfate; side effects include respiratory depression and rarely hypotension
• Nitroglycerin to reduce preload
• Digoxin if in atrial fibrillation
• IV ACE inhibitors
Clinical Recall
What is the most appropriate therapy for the treatment of hypertrophic cardiomyopathy?
Diltiazem
Nifedipine
Lisinopril
Digoxin
Spironolactone
Answer: A
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
159
USMLE Step 2 l Internal Medicine
VALVULAR HEART DISEASE
Mitral Stenosis
Mitral stenosis is the most common lesion caused by rheumatic fever, with possible progression to right ventricular failure. It becomes clinically symptomatic during pregnancy. Mitral stenosis consists of thickened mitral valve leaflets, fused commissures, and chordae tendineae.
Most cases are secondary to rheumatic fever. Rarely, it is caused by a congenital defect, calcification of the valve, or post-radiation treatment to the chest.
Pathogenesis. Mitral valve stenosis impedes left ventricular filling. Increased left atrial pressure is referred to the lungs, causing pulmonary congestion. Forward cardiac output becomes reduced, secondary pulmonary vasoconstriction occurs, and eventually right ventricular failure results.
Clinical Symptoms. Usually manifest slowly over years.
Systemic embolism (due to stagnation of blood in an enlarged left atrium)
Hoarseness (due to impingement of an enlarged left atrium on the recurrent laryngeal nerve)
Atrial fibrillation (irregular cardiac rhythm)
Pulmonary rales
Decreased pulse pressure
Loud S1
Opening snap following S2
Diastolic rumble (low-pitched apical murmur)
Sternal lift (due to right ventricular enlargement)
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
160
Chapter 5 ● Cardiology
Diagnosis is made with the following:
EKG
Possible signs of right ventricular hypertrophy
Possible left and right atrial abnormalities
Atrial fibrillation (common)
Chest x-ray
Large left atrium (indicated by a double-density right heart border, posterior displacement of esophagus, and elevated left mainstem bronchus), straightening of the left heart border
Possible signs of pulmonary hypertension, including Kerley B lines and increased vascular markings
Echocardiography
Thickening of mitral valve leaflets and a reduction in the excursion and area of the valve leaflets
Possible left atrial enlargement
Treatment
Medical Therapy
Digitalis to control the ventricular rate in patients with AF
Balloon valvulotomy is the standard of care for MS
Surgical Management
Indicated when patient remains symptomatic (functional class III) despite medical therapy
Mitral commissurotomy or valve replacement, if balloon dilation fails
Pulmonary hypertension is not a contraindication for surgery
Mitral Regurgitation
Mitral regurgitation is backflow of blood from the left ventricle into the left atrium, due to inadequate functioning (insufficiency) of the mitral valve (most commonly from ischemia). Men are more affected than women.
The etiology of mitral regurgitation is due to abnormalities of the mitral leaflets, annulus, and chordae tendineae. Common causes include hypertension, CHF, ischemic heart disease, rheumatic fever, and any cause of dilation of the left ventricle.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
161
USMLE Step 2 l Internal Medicine
Table 5-8. Acute versus Chronic Etiologies of Mitral Valve Regurgitation
Acute | Chronic |
|
|
A portion of the left ventricular stroke volume is pumped backward into the left atrium instead of forward into the aorta, resulting in increased left atrial pressure and decreased forward cardiac output.
Afterload is decreased as the left ventricle empties part of its contents into the rela- tively low-pressure left atrium.
This helps to compensate for the regurgitation by augmenting ejection fraction.
Left ventricular dysfunction occurs after prolonged compensation.
Dyspnea
Orthopnea
Paroxysmal nocturnal dyspnea
Severe and chronic mitral regurgitation lead to right-sided failure presenting with:
Edema
Ascites
Anorexia
Fatigue
May also have pulmonary hypertension as a late finding.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
162
Chapter 5 ● Cardiology
Physical Signs
• Hyperdynamic and displaced (downward and to the left) left ventricular impulse
• Carotid upstroke diminished in volume but brisk
• Holosystolic apical murmur radiating to the axilla and often accompanied by a thrill
• S3 heard with a soft S1 and widely split S2
• Distended neck veins when severe or acute
Diagnosis
• EKG shows signs of left ventricular hypertrophy and left atrial enlargement.
• Chest x-ray shows cardiac enlargement, with vascular congestion when the regurgita- tion has led to heart failure.
• Echocardiography: The mitral valve can prolapse into the left atrium during systole in cases of a ruptured chordae or mitral valve prolapse. Regardless of the cause, left atrial and left ventricular enlargement occurs if the condition is chronic.
• Catheterization is the single most accurate test.
Treatment. With medical therapy, the goal is to relieve symptoms by increasing forward car- diac output and reducing pulmonary venous hypertension.
• ARBs or hydralazine
• Arteriolar vasodilators (ACE inhibitors)
• Digitalis
• Diuretics
With surgery, mitral valve replacement is used. Guidelines for selecting patients with mitral regurgitation for operation:
• With significantly limiting symptoms and severe mitral regurgitation, surgery is usually indicated. The risk of surgery rises in chronic heart failure.
• In patients with regurgitation who have few or no symptoms, surgery should be deferred. Their condition may remain stable for years.
• Surgery is indicated when symptoms persist despite optimal medical management.
• Criterion is an ejection fraction <60% or left ventricular end systolic diameter >40 mm.
• Repair is preferable to replacement.
Mitral Valve Prolapse
Mitral valve prolapse is the most common congenital valvular abnormality (2–3% population) typically seen in young women. It may occur with greater frequency in those with Ehlers-Dan- los syndrome, polycystic kidney disease, and Marfan syndrome.
Most patients are asymptomatic. Lightheadedness, palpitations, syncope, and chest pain may occur (often due to arrhythmias, which may occur.)
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
163
USMLE Step 2 l Internal Medicine
Clinical Pearl
Look for AS in older patients presenting with syncope related to exertion.
Auscultation
Mid-to-late systolic click and a late systolic murmur at the cardiac apex
Worsens with Valsalva or standing
Improves with squatting or leg raise
Complications (all very rare)
Serious arrhythmias
Sudden death
CHF
Bacterial endocarditis (but does not mean routine dental prophylaxis is indicated)
Calcifications of valve
Transient cerebral ischemic attacks
Lab tests include 2-dimensional/Doppler echocardiography showing marked systolic displace- ment of mitral leaflets with coaptation point at or on the left atrial side of the annulus; moder- ate systolic displacement of the leaflets with at least moderate mitral regurgitation.
Treatment. No specific treatment is needed in most cases. Use beta blockers for chest pain and palpitations. Mitral valve replacement is rarely needed.
Aortic stenosis is most commonly caused by calcification and degeneration of a congenitally normal valve. It is common in the elderly. Other etiologies include:
Calcification and fibrosis of a congenitally bicuspid aortic valve
Rheumatic valvular disease, i.e., if the aortic valve is affected by the rheumatic fever, the mitral valve is also invariably affected
Aortic stenosis results in elevation of left ventricular systolic pressure, and the resultant left ventricular hypertrophy maintains cardiac output without dilation of the ventricular cavity. Therefore, the stroke volume is normal until the late stages of the disease.
Forceful atrial contraction augments filling at the thick, noncompliant ventricle and generates a prominent S4 gallop that elevates the left ventricular end-diastolic pressure.
Left ventricular hypertrophy and high intramyocardial wall tension account for the increased oxygen demands and, along with decreased diastolic coronary blood flow, account for the occurrence of angina pectoris.
As the myocardium fails, mean left ventricular diastolic pressure increases, and symptoms of pulmonary congestion ensue.
Clinical Presentation.
Angina, syncope, and dyspnea from CHF (classic symptoms)
Pulsus tardus et parvus
Carotid thrill
Systolic ejection murmur in aortic area, usually with thrill, harsh quality, radiates to carotids
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
164
Chapter 5 ● Cardiology
• S4 gallop
• A2 decreased, S2 single or paradoxically split
• Aortic ejection click
Diagnosis. EKG often shows left ventricular hypertrophy. Chest x-ray may present with calcification, cardiomegaly, and pulmonary congestion. Echocardiography shows thick aortic valve leaflets with decreased excursion and LVH.
Treatment. Endocarditis prophylaxis is no longer recommended.
• Surgery (valve replacement) is advised when symptoms develop, which is when the valve area is reduced below 0.8 cm2 (normal aortic orifice, 2.5–3 cm2). Generally, if patient has symptoms from stenosis, surgery is the treatment of choice.
• Balloon valvuloplasty may be useful in those too ill to tolerate surgery.
Table 5-9. Differential Diagnosis of Aortic Valve Stenosis
Disease Entity | |
Aortic valve sclerosis of the elderly, without stenosis | No hemodynamically significant aortic valve gradient by cardiac catheterization |
Hypertrophic obstructive cardiomyopathy | |
Mitral regurgitation | Murmur is holosystolic and radiates to axilla and not carotids Carotid upstroke may be normal Dilated left ventricle Aortic valve normal on echocardiogram unless there is associated aortic valve disease |
Pulmonic stenosis | Murmur does not radiate into neck; loudest along the left sternal border; increases with inspiration Physical examination, chest x-ray, and EKG may reveal enlarged right ventricle Echocardiogram reveals right ventricular enlargement and hypertrophy |
Note: All of the above have a systolic murmur that can be confused with aortic stenosis.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
165
USMLE Step 2 l Internal Medicine
Table 5-10. Effect of Various Maneuvers on Systolic Murmurs
Valsalva | Phenylephrine Handgrip | Squatting | Amyl Nitrite | Leg Raising | |
Aortic stenosis | Decrease | Decrease | Increase or decrease | Increase | Increase |
Hypertrophic obstructive cardiomyopathy | Increase | Decrease | Decrease | Increase | Decrease |
Ventricular septal defect | Decrease | Increase | No change | Decrease | Increase |
Mitral regurgitation | Decrease | Increase | Increase | Decrease | Increase |
The most common causes of aortic regurgitation are systemic hypertension and ischemic heart disease.
May result from a condition which affects the ascending aorta: syphilis, ankylosing spondylitis, Marfan syndrome, rheumatic fever, aortic dissection, aortic trauma
Aortic regurgitation results in a volume overload of the left ventricle.
The ventricle compensates by increasing its end-diastolic volume according to the Frank-Starling mechanism.
The left ventricular dilation is thought to overstretch the myofibrils, leading to less actin–myosin interaction and decreased contractility.
In acute severe aortic regurgitation, the left ventricle has not had the opportunity to dilate, its compliance is relatively high, and the aortic regurgitation therefore leads to very high left ventricular end-diastolic pressure.
If mitral regurgitation ensues, the elevated left ventricular diastolic pressure is reflected back to the pulmonary vasculature, and acute pulmonary edema may occur.
Acute aortic regurgitation results in a lower cardiac output, narrower aortic pulse pressure, and a smaller left ventricle than does chronic aortic regurgitation.
Aortic diastolic pressure decreases in chronic aortic regurgitation because of both the regurgitation of blood into the left ventricle and a compensatory decrease in systemic vascular resistance to maintain forward cardiac flow to the periphery. The increased pulse pressure in chronic aortic regurgitation is due to the large stroke volume, causing increased systolic and decreased diastolic pressure.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
166
Chapter 5 ● Cardiology
Clinical Manifestations
• Dyspnea is the most common complaint.
• Diastolic decrescendo murmur is the most typical.
• Systolic flow murmur
• Duroziez sign: systolic and/or diastolic thrill or murmur heard over the femoral arteries
• S3 in early left ventricular decompensation
• Austin-Flint murmur
Diagnosis
• EKG: LV hypertrophy often with volume overload pattern (narrow deep Q waves in left precordial leads)
• Chest x-ray: LV and aortic dilation
• Echocardiography: Dilated LV and aorta; left ventricular volume overload; fluttering of anterior mitral valve leaflet
Treatment. Endocarditis prophylaxis is no longer recommended.
• Salt restriction, diuretics, after load reduction (e.g., ACE inhibitors)
• Aortic valve replacement when symptoms worsen or ejection fraction decreases.
• Vasodilators such as an ACE, ARB, or nifedipine are the standard of care.
• Perform surgery when the ejection fraction is <55% or left ventricular systolic diam- eter is >55 mm.
Clinical Recall
Which of the following is most appropriate in the management of a patient with aortic stenosis?
Surgical replacement when the EF <60% or LV end systolic diameter
>40 mm
Surgical replacement when the valve area <0.8 cm2
Surgical replacement when the EF <55% or LV systolic diameter
>55 mm
None of the above
Answer: C
Note
Remember, aortic regurgitation can cause 3 different murmurs
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
167
USMLE Step 2 l Internal Medicine
MYOCARDIAL DISEASE
Cardiomyopathy
Cardiomyopathy is a disease involving the heart muscle itself. Cardiomyopathies can be classified according to morphologic and hemodynamic characteristics.
Table 5-11. Morphologic and Hemodynamic Characteristics of Cardiomyopathies
Dilated | Hypertrophic | Restrictive | |
Biventricular dilatation | Reduced ventricular compliance; usually caused by infiltration of myocardium (e.g., by amyloid, hemosiderin, or glycogen deposits) | ||
Normal to ↓ | |||
Normal or ↓ | |||
↑ | |||
Normal or ↑ | |||
Normal to ↓ | |||
↓ | |||
May have associated functional mitral or tricuspid regurgita- tion. | Obstruction may develop between interventricular septum and septal leaflet of mitral valve. | Characteristic ventricular pressure tracing that resembles those recorded in constrictive pericarditis, with early diastolic dip-and-plateau configuration |
Dilated (congestive) cardiomyopathy
Characterized by diminished myocardial contractility, usually involving both ventricles; most common cause for heart transplants.
Etiologies of Dilated (Congestive) Cardiomyopathy
Idiopathic: most common
Alcoholic
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
168
Chapter 5 ● Cardiology
• Peripartum
• Postmyocarditis due to infectious agents (viral, parasitic, mycobacterial, Rickettsiae)
• Toxins (cobalt, lead, arsenic)
• Doxorubicin hydrochloride, cyclophosphamide, vincristine
• Metabolic: chronic hypophosphatemia, hypokalemia, hypocalcemia, uremia
Clinical Manifestations. Symptoms and signs of left and right ventricular failure. Typical symptoms of systolic dysfunction.
Diagnosis
• X-ray: cardiomegaly with pulmonary congestion
• EKG: sinus tachycardia, arrhythmias, conduction disturbances
• Echo (key diagnostic study): dilated left ventricle, generalized decreased wall motion, mitral valve regurgitation; transesophageal echo is more sensitive and specific than transthoracic
• Catheterization: dilated hypocontractile ventricle, mitral regurgitation
Treatment. Patients are treated as those with systolic heart failure. ACE, beta blockers, and spironolactone lower mortality. Diuretics and digoxin decrease symptoms. Implantable defibrillator may decrease risk of sudden death when the ejection fraction is <35%.
Hypertrophic Obstructive Cardiomyopathy
Etiology. Although hypertrophic obstructive cardiomyopathy (HOCM) can apparently devel- op sporadically, it is hereditary in >60% of cases and is transmitted as an autosomal dominant trait.
• An abnormality on chromosome 14 has been identified in the familial form of the disease.
• The distinctive hallmark of the disease is unexplained myocardial hypertrophy, usually with thickening of the interventricular septum.
Pathophysiology. As a result of the hypertrophy, left ventricular compliance is reduced, but systolic performance is not depressed. Diastolic dysfunction is characteristic, resulting in decreased compliance and/or inability for the heart to relax.
• The heart is hypercontractile, and systole occurs with striking rapidity.
• Ejection fractions are often 80–90% (normal is 60%, ±5%), and the left ventricle may be virtually obliterated in systole.
• The ability to provoke obstruction or increase/decrease already existing obstruction is influenced by several factors.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
169
USMLE Step 2 l Internal Medicine
Table 5-12. Factors That Modify Obstruction in Hypertrophic Obstructive Cardiomyopathy
Increase Obstruction | Decrease Obstruction | ||
Mechanism | Physiologic or Pharmacologic Factors | Mechanism | Physiologic or Pharmacologic Factors |
Increase in contractility | Tachycardia Digitalis glycosides β-adrenergic stimulation (e.g., epinephrine, exercise) Premature beats | Decrease in contractility | β-adrenergic blockade Heavy sedation and general anesthesia Calcium channel blockers, disopyramide, and other drugs that depress myocardial function |
Valsalva maneuver | Intravascular volume expansion Squatting | ||
Bradycardia | |||
β-adrenergic blockade | |||
Intravascular volume expansion Squatting | |||
α-adrenergic stimulation (e.g., phenylephrine) | |||
Handgrip | |||
Dyspnea, angina, presyncope, syncope with exertion, and palpitations
Large jugular A wave, bifid carotid pulse, palpable S4 gallop, systolic murmur and thrill, mitral regurgitation murmur
Sudden death can sometimes be the first manifestation.
Diagnosis
EKG: left ventricular hypertrophy, pseudo Q waves (often seen V1–V3), ventricular arrhythmias
Echocardiogram is the mainstay of diagnosis. It typically shows hypertrophy, systolic anterior motion of mitral valve, and midsystolic closure of aortic valve
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
170
Chapter 5 ● Cardiology
Treatment
• Beta-blockers
• Calcium channel blockers that reduce heart rate: diltiazem, verapamil
• Disopyramide, occasionally
• Use implantable defibrillator if there is syncope
• Surgery in severe cases—septoplasty
Restrictive Cardiomyopathy
Restrictive cardiomyopathy is the least common of the causes of cardiomyopathy. It is myocardial disorder characterized by rigid noncompliant ventricular walls.
Etiologies
• Infiltrative: sarcoidosis/amyloidosis; hemochromatosis; neoplasia
• Scleroderma
• Radiation
Pathophysiology. The myocardium is rigid and noncompliant, impeding ventricular filling and raising cardiac filling pressures from abnormal diastolic function. Systolic performance is often reduced, but the overriding problem is impaired diastolic filling, which produces a clinical and hemodynamic picture that mimics constrictive pericarditis.
Clinical Manifestations
• Dyspnea, exercise, intolerance, weakness
• Elevated jugular venous pressure, edema, hepatomegaly, ascites, S4 and S3 gallop, Kussmaul sign
Diagnosis
• X-ray: mild cardiomegaly, pulmonary congestion
• EKG: low voltage, conduction disturbances, Q waves
• Echo: characteristic myocardial texture in amyloidosis with thickening of all cardiac structures
• Catheterization: square root sign; elevated left- and right-sided filling pressures
Treatment. There is no good therapy; ultimately results in death from CHF or arrhythmias; consider heart transplantation.
Clinical Pearl With HOCM, avoid the following:
Digitalis
Diuretics
Vasodilators
Exercise
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
171
USMLE Step 2 l Internal Medicine
PERICARDIAL DISEASE
Acute Pericarditis
Acute pericarditis is inflammation of the pericardial lining around the heart.
V4
V1
R
a
Figure 5-12. Acute Pericarditis with Diffuse ST Segment Elevation
Trauma
Inflammation (uremia)
Clinical Manifestations. Chest pain, often localized substernally or to the left of the sternum, is usually worsened by lying down, coughing, and deep inspiration (which helps in the differential diagnosis with MI) and is relieved by sitting up and leaning forward.
Pericardial friction rub (diagnostic of pericarditis) is a scratchy, high-pitched sound that has 1 to 3 components corresponding to atrial systole, ventricular systole, and early diastolic ventricular filling. The ventricular systole component is present more consistently. The rub is often transient and is best heard with the diaphragm of the stethoscope as the patient sits forward at forced-end expiration.
Diagnosis. EKG may be diagnostic and reveals a diffuse ST-segment elevation with upright T waves at the onset of chest pain. PR segment depression is very specific. The diffuseness of the
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
172
Chapter 5 ● Cardiology
ST-segment elevation, absence of reciprocal leads, and absence of the development of Q waves
distinguish the characteristic pattern of acute pericarditis from the pattern seen in acute MI.
Treatment of acute pericarditis involves treating its etiology. In idiopathic pericarditis, treat with anti-inflammatory medications (NSAIDs, aspirin, corticosteroids). Adding colchicine to an NSAID decreases recurrence.
Pericardial Effusion
Fluid may accumulate in the pericardial cavity in virtually all forms of pericardial disease. The fluid may be a transudate, as are the serous cavity effusions that develop in patients with CHF, overhydration, or hypoproteinemia. More often, however, the pericardial effusion is an exu- date, reflecting the presence of pericardial injury.
• Serosanguineous pericardial fluid is a classic sign in tuberculosis and neoplastic diseases.
• Frank blood in the pericardial space may occur in cases of aortic aneurysm or aortic dissection.
• Hemopericardium may also be produced by closed or penetrating trauma, rupture of the heart in acute MI, and bleeding caused by coagulation defects.
• When fluid accumulates slowly, the pericardium expands to accommodate it. When
fluid accumulates rapidly, however, it compresses the heart and inhibits cardiac filling (cardiac tamponade).
Diagnosis. Echocardiography is the most effective laboratory technique available. The presence of pericardial fluid is recorded as a relatively echo-free space between the posterior pericardium and the posterior left ventricular epicardium in patients with small effusions. In patients with large effusions, the heart may swing freely within the pericardial sac, and this motion may be associated with electrical alternans.
Chest x-ray may show a “water-bottle” configuration of the cardiac silhouette.
Treatment. Treatment includes fluid aspiration and management of the etiology.
Cardiac tamponade
Cardiac tamponade is a life-threatening condition in which a pericardial effusion has devel- oped so rapidly or has become so large that it compresses the heart.
Etiology
• Neoplasia
• Idiopathic (usually viral) pericarditis
• Nonviral infection: tuberculous; suppurative
• Intrapericardial hemorrhage with or without pericarditis
• Wounds, including surgery of chest; heart; pericardium
• Postpericardiotomy syndrome
• Uremia
• Mediastinal and juxtamediastinal radiation therapy
• Vasculitis–connective tissue disease group
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
173
USMLE Step 2 l Internal Medicine
Clinical Manifestations. Most patients with cardiac tamponade complain of dyspnea, fatigue, and orthopnea.
Pulsus paradoxus, characterized by a decrease in systolic blood pressure >10 mm Hg with normal inspiration (very common)
The paradoxical pulse often can be noted by marked weakening or disappearance of a peripheral pulse during inspiration.
Paradoxical pulse is not diagnostic of cardiac tamponade; it can occur in chronic lung disease, acute asthma, severe CHF, and even hypovolemic shock.
Neck vein distension with clear lung
Shock (hypotension)
Decreased heart sounds
Beck’s triad is associated with acute tamponade: low blood pressure, distended neck veins, and decreased heart sounds
Diagnosis. Clinical manifestations followed by echocardiography and cardiac catheterization, which confirms that left and right atrial pressures are equal.
Treatment. Treat with pericardiocentesis and subxiphoid surgical drainage.
Constrictive pericarditis is the diffuse thickening of the pericardium in response to prior inflammation, resulting in reduced distensibility of the cardiac chambers.
Cardiac output is limited and filling pressures are increased to match the external constrictive force placed on the heart by the pericardium.
The fundamental hemodynamic abnormality is abnormal diastolic filling.
Postviral infection
Clinical Manifestations. Most patients complain of dyspnea on exertion due to limited cardiac output. Orthopnea occurs in about 50% of patients. Symptoms and signs related to systemic venous hypertension are often reported: ascites, edema, jaundice, hepatic tenderness, and hepatomegaly (manifestations of right-side failure). Jugular venous distension increases with inspiration (Kussmaul sign). Heart sounds are distant, and an early diastolic apical sound, or “pericardial knock,” is often present and can be confused with an S3 gallop.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
174
Chapter 5 ● Cardiology
Diagnosis
• EKG: low-voltage and nonspecific T-wave changes
• Chest x-ray: heart is usually normal in size
• Chest CT or MRI: thickened pericardium; pericardial calcifications may be seen in tuberculous constriction
• Cardiac catheterization
– Marked “y” descent is present in right atrial pressure tracing
– Characteristic “dip and plateau” or “square root” sign is present in left and right ventricular pressure tracing
– Equalization of end-diastolic pressures in all 4 chambers and pulmonary artery
It is sometimes difficult to distinguish constrictive pericarditis from restrictive cardiomyopa- thy. Left ventricular ejection fraction is more likely to be decreased in the latter. CT is the procedure of choice to demonstrate the thickened pericardium.
Treatment. Treated conservatively at first with mild sodium restriction and diuretics. Pericardiectomy may be needed.
Clinical Recall
Echocardiography showing ventricular wall thickening with a Kussmaul sign
Echocardiography showing echo-free space between the posterior pericardium and the posterior LV epicardium with distant muffled heart sounds
EKG showing a decrease in SBP >10 mm Hg with normal inspiration
EKG showing diffuse ST-segment elevation with PR segment
depression
Answer: E
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
175
USMLE Step 2 l Internal Medicine
RATE AND RHYTHM DISTURBANCES
Disorders of Sinus Node Function
Sinus bradycardia
Ventricular complexes are normal width, evenly spaced, rate <60/min.
Etiology
Excessive vagal tone causes: acute MI (particularly diaphragmatic); carotid sinus pressure; vomiting; Valsalva maneuver; phenothiazines; digitalis glycosides
Depression of sinus node automaticity: beta-adrenergic blocking agents; calcium- blocking drugs
Treatment. In the absence of symptoms, no treatment is needed. If symptoms are present, administer atropine acutely. If symptoms and bradycardia still continue, consider a pacemaker.
Atrioventricular (AV) block can be classified in 2 ways: anatomical (based on site of block as determined by His bundle electrocardiography) or clinical (based on the routine ECG). The classic clinical types are first-, second-, and third-degree (or complete) AV block.
First-degree AV block is pulse rate (PR) interval >0.20 s at heart rate 70 beats/min. It is caused by a cardiomyopathy or by a degenerative change in the AV conduction system due to aging, digitalis, exaggerated vagal tone, ischemia (diaphragmatic infarction, or inflammation (myo- carditis, acute rheumatic fever).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
176
Chapter 5 ● Cardiology
Table 5-13. Type I versus Type II Second-Degree AV Block
Type I (Mobitz I, Wenckebach) | Type II (Mobitz II) | |
Mobitz Type I R R R R P P P P P Dropped Beat | Mobitz Type II | |
R R R | ||
P P P | ||
Dropped Beat | ||
Site of block | Infranodal (intra- or infra-Hisian) | |
QRS complex | Usually wide (bundle branch block) with infra- Hisian block; narrow with intra-Hisian block | |
Causes | Extensive anterior myocardial infarct; degenera- tive changes in His-Purkinje system; massive calcification of mitral or aortic valve anulus | |
EKG | PR interval lengthens progressively until ventricu- lar beat is dropped | PR interval is usually normal in duration and constant in length if PR interval is prolonged, the duration of prolongation is fixed Blocked beats occur suddenly without progres- sive lengthening of the PR interval RR interval of conducted beats is constant or a multiple of a basic RR interval cycle length |
Effect of carotid sinus pressure | ||
Effect of atropine | Frequently shortens PR interval and increases AV conduction | No effect |
Consequences of | Escape focus usually junctional; narrow QRS | Escape focus infrajunctional (usually ventricular) |
progression to | complex; rate >45 beats/min; Adams-Stoke | wide QRS complex; rate <45 beats/min; Adams- |
complete heart | attacks uncommon | Stoke attacks common |
block | ||
Junctional escape may be present with intra- Hisian block |
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
177
USMLE Step 2 l Internal Medicine
Third-Degree (Complete) AV Block
In third-degree (complete) heart block, all atrial beats are blocked, and the ventricles are driven by an escape focus distal to the site of block.
Figure 5-13. Third-Degree AV Block
The most common cause in adults is simple fibrous degenerative changes in the conduction system as a result of aging (Lenègre disease).
Infectious and inflammatory processes, such as abscesses, tubercles, tumors, infiltra- tive disease of the myocardium, sarcoid nodules, and gummas, myocarditis, and rheumatic fever
Clinical Manifestations. Symptoms are associated with Adams-Stoke attacks and occasionally CHF. Adams-Stoke attacks are caused by sudden asystole or the development of a ventricular tachyarrhythmia (transient ventricular tachycardia or ventricular fibrillation), leading to circulatory arrest. The bradycardia associated with complete heart block may lead to conges- tive heart block in patients with myocardial disease.
Sinus tachycardia is defined as a normal rhythm with a rate of >100 beats/minute. The ventricular complexes are of normal width, evenly spaced, and a P-wave precedes a QRS complex. It usually represents a physiologic response to fever, hypotension, volume depletion, anxiety, and pain. Other causes include thyrotoxicosis, anemia, and some drugs.
Transient sinus tachycardia is occasionally the result of a rebound phenomenon following the discontinuation of beta-adrenergic blocking drugs.
Paroxysmal supraventricular tachycardia is a group of ectopic tachyarrhythmias character- ized by sudden onset and abrupt termination. They are usually initiated by a supraventricular premature beat (includes paroxysmal atrial tachycardia)
80% are caused by re-entry, mainly in the AV node.
Manifests as an absolutely regular rhythm at a rate 130–220 beats/min (average 160).
Initial therapy consists of maneuvers aimed at increasing vagal tone, particularly right carotid sinus massage. Carotid sinus massage is followed by adenosine.
IV adenosine is effective in >90% of cases.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
178
Chapter 5 ● Cardiology
• IV propranolol or esmolol, verapamil
• IV digitalis
• Synchronized external cardioversion if patient is unstable
Multifocal atrial tachycardia is characterized by an irregular supraventricular rhythm, at rates 100–200 beats/min.
• The morphology of the P waves (at least 3 different P wave forms) varies from beat to beat, as does the PR interval. Each QRS complex, however, is preceded by a P wave.
• Generally seen in elderly patients or those with chronic lung disease who are experi- encing respiratory failure
• Use diltiazem, verapamil, or digoxin; avoid beta blockers because of lung disease
Atrial flutter generally presents as an absolutely regular rhythm with a ventricular rate 125–150 beats/min and an atrial rate 250–300 beats/min (i.e., 2:1 block). It has been associated with:
• Chronic obstructive lung disease
• Pulmonary embolism
• Thyrotoxicosis
• Mitral valve disease
• Alcohol
• Paroxysmal arrhythmia in persons with normal heart
Therapy is cardioversion if hemodynamically unstable (e.g., hypotension), digitalis, verapamil, diltiazem, and beta-blockers.
Figure 5-14. Atrial Flutter
Atrial Fibrillation
Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance. It is associated with heart disease but also occurs with no detectable disease. Thromboembolic events occur with AF and can cause significant morbidity and mortality.
Figure 5-15. Atrial Fibrillation
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
179
USMLE Step 2 l Internal Medicine
AF is a supraventricular tachyarrhythmia characterized by uncoordinated atrial activation with subsequent decline of atrial function.
On ECG, there is replacement of consistent P waves by fibrillatory waves that vary in size, shape, and timing, associated with an irregular, frequently rapid ventricular response (irregularly, irregular).
The ventricular response to AF depends on electrophysiologic properties of the AV node, the level of vagal and sympathetic tone, and the action of drugs.
Extremely rapid rates (>200 bpm) suggest the presence of an accessory pathway (W-P-W syndrome), which may manifest as AF.
The rate of ischemic stroke among patients with nonrheumatic AF averages 5% per year, which is 2–7x the rate for people without AF.
The CHADS score is a clinical prediction rule for estimating the risk of stroke in a patient with AF. It is used to determine whether treatment is required with anticoagulation or anti- platelet therapy. A high CHADS score corresponds to a greater risk of stroke.
C for CHF, H for hypertension, A for age >75, D for diabetes, S for prior stroke or TIA
Each condition receives 1 point except prior stroke, which gets 2.
| |
When AF is compared with atrial flutter, atrial flutter is found to be more organized than AF, with a sawtooth pattern of regular atrial activation called flutter (f) waves on the ECG, particularly visible in leads II, III, and aVF.
The diagnosis of AF should be considered in elderly patients who present with complaints of shortness of breath, dizziness, or palpitations. The arrhythmia should also be suspected in patients with acute fatigue or exacerbation of CHF. In some patients, AF may be identified on the basis of an irregularly irregular pulse or ECG obtained for another condition.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
180
Chapter 5 ● Cardiology
New onset AF
Hemodynamically stable
(no hypotension, no acute heart failure, etc.)
Yes
No
Control rate (<110 beats/min) with diltiazem, verapamil, beta-blocker, or digoxin
Cardioversion: sedate before (100J, 200J, 300J
until sinus rhythm returns)
Consider anticoagulation after patient is stable
Yes
Assess cause and follow-up
Consider cardioversion (electrical or pharmacologic)
AF recurs
Observe off anticoagulation
Long-term anticoagulation and rate control
May consider rhythm control: ablation, cardioversion
Figure 5-16. Management of Atrial Fibrillation (AF)
Cardiac conditions commonly associated with the development of AF include rheumatic mitral valve disease, coronary artery disease, CHF, and hypertension (cause atrial structures to dilate). Noncardiac conditions which can predispose patients to develop AF include hyperthy- roidism, hypoxemia, and alcohol intoxication.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
181
USMLE Step 2 l Internal Medicine
Note
Routine rhythm control for AF is not indicated. It is an exception.
Evaluation of Patients with AF (Minimum Workup):
H and P: identifies severity of symptoms associated with AF, as well as the clinical type (paroxysmal, persistent, first episode); also allows assessment of frequency and duration of AF, as well as identification of precipitating factors and presence of underlying heart or lung disease
ECG: verifies the rhythm as well as identifies LVH, pre-excitation, prior MI
Chest x-ray: allows evaluation of lung parenchyma and identifies coexisting lung disease
Echocardiogram: identifies LVH, valvular disease, atrial size, and possible left atrial thrombus.
Thyroid function tests: excludes hyperthyroidism as a cause of AF
Management. Two general approaches are used to manage AF:
Rhythm control (attempts to convert to and maintain sinus rhythm)
There is little difference in mortality between rate control and pharmacologic rhythm control. Studies confirm the importance of anticoagulation to reduce the risk of stroke in patients with AF. Interestingly, <25% of patients on an antiarrhythmic regimen remained in sinus rhythm at the end of 1 year. The standard of care is to slow the rate and anticoagulate if CHADS score >1.
As a general concept, rate control alone is considered for the patient who notices very few of the symptoms of the arrhythmia, while rhythm control is applied to the patient who immedi- ately notices the arrhythmia and is experiencing the consequences (shortness of breath, or development of heart failure).
Cardioversion (rhythm control)—mechanical cardioversion involves an electrical shock synchronized with the intrinsic activity of the heart. The synchronization ensures that electrical stimulation does not occur during the vulnerable phase of the cardiac cycle.
May be performed electively to restore sinus rhythm in patients with persistent AF
May be performed for immediate need, i.e., when arrhythmia is main factor respon- sible for hemodynamic instability (acute heart failure, hypotension, or angina)
Carries a risk of thromboembolism, so in cases of elective cardioversion, initiate anticoagulation before the procedure
Cardioversion (rhythm control)—pharmacologic cardioversion can be achieved with drugs. It is less effective than electrical cardioversion, but it does not require conscious seda- tion or anesthesia, as does mechanical cardioversion.
Carries a risk of thromboembolism, so initiate anticoagulation
Drugs proven effective for AF include amiodarone, dofetilide, flecainide, ibutilide, propafenone, and quinidine
Drugs used to maintain sinus rhythm in patients with AF include amiodarone, disopyramide, dofetilide, flecainide, propafenone, and sotalol
Rate control is the standard of care for most patients.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
182
Chapter 5 ● Cardiology
Catheter ablation of AF foci is sometimes used as one of the nonpharmacologic therapies for eradicating AF. The techniques evolved with the demonstration that most AF is initiated by ectopic beats from focal areas that may be targeted for ablation. These foci arise more commonly from the 4 pulmonary veins. Thus, techniques have focused on the identification and elimination of these foci.
Ventricular rate control to achieve a rate of <100–110 beats/min is one of the first steps in managing AF. Beta blockers, calcium channel blockers, and digoxin are the drugs most commonly used for rate control. These agents do not convert atrial fibrillation to sinus rhythm and should not be used for that purpose. Beta blockers and calcium channel blockers are effective in reducing the heart rate at rest and during exercise in patients with AF. Digoxin, because of the inotropic effects, is the drug of choice in patients with coexisting systolic heart failure. Factors that should guide drug selection include the patient’s medical condition and the presence of concomitant heart failure. The following drugs are recommended for their demonstrated efficacy in rate control at rest and during exercise: diltiazem, atenolol, metopro- lol, and verapamil.
Rate control with chronic anticoagulation is the recommended strategy for the majority of patients with chronic AF. Rhythm control has not been shown to be superior to rate control (with chronic anticoagulation) in reducing morbidity and mortality.
Control the heart rate, then anticoagulate. Use aspirin for those with CHADS 0 or 1, and dabigatran, rivaroxaban, or warfarin for CHADS 2 or more. Heparin is not necessary prior to starting oral anticoagulants.
Patients with AF should receive chronic anticoagulation with dabigatran, rivaroxaban, or adjusted-dose warfarin, unless they have a specific contraindication.
The goals of initial management are hemodynamic stabilization, ventricular rate control, and prevention of embolic complications. When AF does not terminate spontaneously, the ventricular rate should be treated to slow ventricular response and anticoagulation started.
Pre-excitation syndrome
Wolff-Parkinson-White Syndrome (WPW)
Pre-excitation is a condition in which all or some portion of the ventricle is activated by atrial impulses earlier than if the impulses were to reach the ventricles by way of the normal cardiac conduction pathways. This is achieved by the use of accessory pathways (Kent bundle).
Classically, EKG shows a short PR interval followed by a wide QRS complex with a slurred initial deflection, or delta wave, representing early ventricular activation.
WPW is associated with paroxysmal supraventricular arrhythmias alternating with ventricular arrhythmias, AF, and atrial flutter.
Treatment. If the patient is hemodynamically unstable, then immediate electrical cardiover- sion is indicated (synchronized cardioversion). If hemodynamically stable, use procainamide. Avoid digoxin, beta blockers, and calcium-channel blockers, as they can inhibit conduction in the normal conduction pathway. That could increase the likelihood of developing ventricu- lar or supraventricular tachycardia.
If conduction is inhibited in the normal pathway, that will increase conduction in the aberrant conduction pathway. Ablation is used as definitive treatment.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
183
USMLE Step 2 l Internal Medicine
aVR V1 V4
aVL V2 V5
II
aVF
V3 V6
Figure 5-17. Wolff-Parkinson-White Syndrome
Ventricular tachycardia (VT) is defined as ≥3 consecutive beats of ventricular origin at a rate
>120 beats/min. QRS complexes are wide and often bizarre.
Cardiomyopathies and rarely seen in patients with mitral valve prolapse
Metabolic derangements, such as hypokalemia, hypercalcemia, hypomagnesemia, and hypoxia
Digitalis toxicity and thioridazine drugs
Clinical Presentation. Patients with VT often present with concomitant hypotension, CHF, syncope, or cardiac arrest.
Independent and asynchronous atrial and ventricular contractions produce the follow- ing signs. These signs are absent when AF is present.
Variation in systolic blood pressure, as measured peripherally
Variation in intensity of the heart sounds
Intermittent cannon A waves in jugular venous pulses caused by the simultaneous contraction of the atrium and ventricles
Extra heart sounds
Because of asynchronous activation of the right and left ventricles, the first and second sounds are widely split.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
184
Chapter 5 ● Cardiology
Table 5-14. QRS Complex
Wide (>0.12 s) | Narrow (<0.12 s) | ||
Regular | Irregular | Regular | Irregular |
Ventricular tachycardia | Atrial fibrillation (rarely) | Sinus tachycardia | Atrial fibrillation |
Supraventricular tachycardia (aberration) | Paroxysmal supraventricular tachycardia | Multifocal atrial tachycardia | |
Wolff-Parkinson-White syndrome | Atrial flutter | ||
Stable
O2
IV access
Amiodarone or lidocaine
Lidocaine until VT resolves
Procainamide until VT resolves
Cardiovert 200 J
Cardiovert if patient becomes unstable
Cardiovert 300 J
Cardiovert 360 J
Figure 5-18. Management of VT
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
185
USMLE Step 2 l Internal Medicine
Clinical Recall
Which of the following is the most appropriate management in the treatment of Wolf-Parkinson-White syndrome?
Procainamide
Propranolol
Verapamil
Nimodipine
Sotalol
Answer: A
Torsade de Pointes is characterized by undulating rotations of the QRS complexes around the electrocardiographic baseline. Arrhythmias are initiated by a ventricular premature beat in the setting of abnormal ventricular repolarization characterized by prolongation of the QT interval.
Figure 5-19. Torsade de Pointes
Etiology. Antiarrhythmic drugs that prolong ventricular repolarization include:
Procainamide
Disopyramide
Psychotropic drugs: phenothiazines, thioridazine, tricyclics, lithium
Electrolyte imbalance: hypokalemia, hypomagnesemia
CNS lesion: subarachnoid or intracerebral hemorrhage
Clinical Presentation. Patients with long QT interval are prone to recurrent dizziness or syncope from the ventricular tachycardia.
Sudden auditory stimuli, such as the ringing of the telephone at night, may initiate Torsade de Pointes in a vulnerable individual with a long QT interval syndrome.
Treatment. Treat the underlying disorder. In the case of the antiarrhythmics, use a drug such as lidocaine. With electrolyte imbalance disorders, replace potassium and magnesium. Cardiac pacing or isoproterenol infusion may suppress episodes of tachycardia, useful for emergency treatments. If hemodynamically unstable (e.g., hypotension), consider cardioversion (but this
USMLE® isdayjsorihnyttphrmogiraaomftoefnTrheeoFcecduerrsa)t.ion of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
186
Chapter 5 ● Cardiology
Ventricular Fibrillation
See the Emergency Medicine section.
1
Pulseless Arrest
BLS Algorithm: call for help, give CPR
Give oxygen when available
Attach monitor/defibrillator when available
3 2 9
VF/VT
Check rhythm
Shockable rhythm?
Asystole/PEA
Give 1 shock
Resume CPR | |
4 
Resume CPR immediately for 5 cycles When IV/IO available, give vasopressor
Repeat every 3 to 5 min | |
Give 5 cycles of CPR* | |
10
5 
Continue CPR while defibrillator is charging Give 1 shock
Resume CPR immediately after the shock When IV/IO available, give vasopressor during CPR (before or after the shock) Repeat every 3 to 5 min or | |
Check rhythm Shockable rhythm? | |||
Shockable | |||
13 | |||
If pulse present, begin postresuscitation care
Go to Box 4
Check rhythm
Shockable rhythm?
7 No
Shockable
8
Push hard and fast (100/min)
Ensure full chest recoil
Continue CPR while defibrillator is charging
Give 1 shock
Manual biphasic: device specific (same as first shock or higher dose; if unknown, use 200 J)
AED: device specific
Monophase: 360 J
Resume CPR immediately after the shock, consider antiarrhythmics; give during CPR
(before or after the shock)
amiodarone or lidocaine
Consider magnesium for torsades de pointes
After 5 cycles of CPR,* go to Box 5 above
Minimize interruptions in chest compressions
One cycle of CPR: 30 compressions then 2 breaths; 5 cycles = 2 min
Avoid hyperventilation
Secure airway and confirm placement
After an advanced airway is placed, rescuers no longer deliver “cycles” of CPR. Give continuous chest compressions without pauses for breaths. Give 8–10 breaths/minute. Check rhythm every 2 minutes.
Rotate compressors every
2 minutes with rhythm checks
Search for and treat possible contributing factors:
–Hypovolemia
–Hypoxia
–Hydrogen ion (acidosis)
–Hypo-/hyperkalemia
–Hypoglycemia
–Hypothermia
–Toxins
–Tamponade, cardiac
–Thrombosis (coronary or pulmonary)
–Trauma
Figure 5-20. ACLS Pulseless Arrest Algorithm
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
187
USMLE Step 2 l Internal Medicine
DRUGS FOR TREATING CARDIOVASCULAR DISEASE
Amiodarone
Amiodarone is a very effective antiarrhythmic drug and can be used in ventricular tachycardia, AF, and atrial flutter. Because it has a long half-life (>50 days), drug interactions are possible for weeks after discontinuation.
The most severe side effects of amiodarone therapy are related to the lungs; they present as cough, fever, or painful breathing. These reactions can be fatal. About 20% of patients who receive amiodarone experience some form of nerve toxicity. Symptoms may include imbalance or changes in gait, tremor, numbness in the fingers or toes, dizziness, muscle weakness, or loss of coordination. Thyroid dysfunction is also common, since the drug molecule is chemically related to thyroxine. Hypothyroidism seems to be more common, but hyperthyroidism can also occur. Since many patients experience an exaggerated response to the harmful effects of sunlight, avoidance of extensive sun exposure and the use of protective clothing should be used to help prevent this.
Long-term administration of amiodarone may occasionally result in a blue-gray discoloration of the skin. This effect seems to be more common in patients with fair skin. Patients also may experience visual impairment or other disturbances such as “halo lights” and blurred vision. Corneal deposits (microdeposits) occur in virtually all patients who receive amiodarone for at least 6 months.
In low doses, nitrates increase venous dilation and subsequently reduce preload. In medium doses, they increase arteriolar dilatation and subsequently decrease afterload and preload. In high doses, they increase coronary artery dilatation and subsequently increase oxygen supply.
Side effects of nitrates include orthostatic hypotension, reflex tachycardia, throbbing headache, and blushing—all caused by vasodilation. Nitrates are contraindicated if systolic BP <90 mm Hg. There must be a window-free period of >8 hours with nitrate therapy to reduce the incidence of tachyphylaxis.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
188
Chapter 5 ● Cardiology
Antiarrhythmic Drugs 
Table 5-15. Antiarrhythmic Drugs
Drug | Adverse Effects |
Disopyramide | Anticholinergic effects; hypotension; heart failure; heart block; tachyarrhythmia |
Lidocaine | CNS (drowsiness, agitation, seizures); heart block |
Phenytoin | CNS (ataxia, nystagmus, drowsiness); hypotension and heart block with rapid IV injection |
Procainamide | Lupus-like syndrome; GI; rash; hypotension; aggravation of arrhythmia; blood dyscrasias |
Quinidine | Aggravation of arrhythmias (“quinidine syncope”); thrombocytopenia; fever, rash; cinchonism; GI symptoms; digoxin-quinidine interaction (elevation of digoxin levels) |
β-adrenergic blocking agents | Heart block; hypotension; asthma; hypoglycemia; lethargy; impotence |
Verapamil | |
Adenosine | Transient dyspnea, noncardiac chest pain, rarely hypotension |
Mexiletine | |
Tocainide | |
Amiodarone | |
Encainide | |
Flecainide | |
Propafenone |
Beta Blockers
Beta blockers have been shown to improve survival after an acute MI and in CHF. They decrease heart rate, BP, and contractility, which decrease myocardial oxygen requirement. They are contraindicated in presence of severe asthma in about 35% of patients.
Nonselective beta blockers may mask hypoglycemic symptoms in insulin-dependent diabetics.
Beta blockers can cause fatigue/insomnia, mental depression, lipid abnormalities, hallucina- tions, Raynaud phenomenon, bronchoconstriction, mask signs/symptoms of insulin-induced hypoglycemia, and sexual dysfunction.
Nebivolol is a unique beta blocker; it is a beta-1 specific blocker that increases nitric oxide and thus does not cause erectile dysfunction.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
189
USMLE Step 2 l Internal Medicine
Table 5-16. Pharmacologic Properties of Select
β-Blocking Agents
Generic Name (Trade Name) | Cardio-Selective |
Metoprolol (Lopressor) | Yes |
Atenolol (Tenormin) | Yes |
Propranolol (Inderal) | No |
Nadolol (Corgard) | No |
Timolol (Blocadren) | No |
Pindolol (Visken) | No |
Calcium channel blockers work by decreasing preload and afterload. They may be harmful in the postinfarction period, especially if the patient has left ventricular failure. Their efficacy in angina is very limited—there is no mortality benefit.
Adverse effects of calcium channel blockers can be cardiac and noncardiac:
Cardiac: CHF, reflex tachycardia, hypotension, lightheadedness, AV block
Noncardiac: flushing, headache, weakness, constipation, nasal congestion, wheezing, peripheral edema, gingival hyperplasia
Shock is a broad term that describes a state where oxygen delivery to the tissues is inadequate to meet the demands. It could be described as the imbalance between tissue oxygen supply and demand.
Four general types of shock syndromes are recognized: distributive, cardiogenic, hypovolemic, and obstructive. There are many etiologies within each class.
Distributive shock: caused by pathologic peripheral blood vessel vasodilation
Examples are sepsis (especially gram-negative), anaphylaxis, neurogenic
Septic shock is most common form of shock among those admitted to ICU (fol- lowed by cardiogenic and hypovolemic shock)
Cardiogenic shock: related to impaired heart pump function
Examples are acute coronary syndrome, valve failure (especially acute) and dys- rhythmia
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
190
Chapter 5 ● Cardiology
Hypovolemic shock: caused by decreased circulatory volume
Examples are hemorrhage (GI bleed) and fluid loss
Obstructive shock: non-cardiac obstruction to blood flow
Examples are pulmonary embolus, tension pneumothorax, and cardiac tamponade The diagnosis of shock is a clinical diagnosis.
Table 5-17. Physiologic Characteristics of Various Forms of Shock
Type of Shock | Heart Rate | Central Venous Pressure | Contractility | Systemic Vascular Resistance |
Cardiogenic | ↑ | ↑ | ↓↓ | ↑ |
Hypovolemic | ↑ | |||
Distributive (sepsis) | ↑ | |||
Obstructive | ↑ |
In all of the forms above, cardiac output decreases; the only exceptions are the hyperdynamic state of septic shock and rarely traumatic shock, both of which may have elevated cardiac output.
Treatment should begin emergently since early therapy has been shown to improve outcomes.
Start with the ABCs and strongly consider intubation in most cases of shock for airway protection.
Circulatory support with IV fluids is paramount in most cases; use caution with rapid fluid administration to the patient with cardiogenic shock and pulmonary edema.
Consider transfusion of blood products in certain types of shock.
If volume resuscitation does not improve hemodynamic status, consider epinephrine, dopamine, or vasopressin.
Furthermore, aggressive treatment of the underlying cause of the shock is warranted, e.g., sepsis syndromes should be treated with broad-spectrum antibiotics, while obstructive shock due to PE may need thrombolysis and anticoagulation.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
191
USMLE Step 2 l Internal Medicine
Clinical Recall
Which of the following is a side effect of amiodarone?
Constipation
Orthostatic hypotension
Pulmonary fibrosis
Thrombocytopenia
Major depression
Answer: C
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
192
CHheamptaetroTloitglye #6
Learning Objectives
List the types of anemia and describe their pathophysiology, diagnosis, and treatment
Describe the presentation and diagnosis of hematologic neoplasias including acute leukemia, chronic leukemias, plasma cell disorders, and lymphomas
List defects that can occur in the coagulation cascade and their associated disorders
ANEMIA
Anemia is a condition marked by the following:
Hemoglobin <13.5 g/dL in men or <12 g/dL in women
Etiology. Anemias are most easily classified according to their cell size.
Microcytic anemia means a low mean corpuscular volume (MCV) <80. It is most commonly a result of iron deficiency, anemia of chronic disease, thalassemia, sideroblas- tosis, or lead poisoning. Anemia of chronic disease can be either microcytic or normo- cytic.
Macrocytic anemia is characterized by an elevated MCV >100. This is most commonly from vitamin B12 or folic acid deficiency but can also result from the toxic effects of alcohol, liver disease, or chemotherapeutic agents such as methotrexate or medications such as zidovudine (AZT) or phenytoin.
Normocytic anemia is characterized by a normal MCV. It can be caused by an early form of the conditions described, as well as most forms of hemolysis and aplastic anemia.
Clinical Presentation. The symptoms of anemia tend to be based on the severity of the anemia rather than the specific etiology. Early symptoms include fatigue and poor exercise tolerance. As the anemia worsens, there is dyspnea on exertion and lightheadedness. Eventually, confusion and altered mental status may develop as oxygen delivery to the brain decreases. Death from anemia is most often caused by decreased oxygen delivery to the heart and resulting myocardial ischemia.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
193
USMLE Step 2 l Internal Medicine
The severity of symptoms is related to the underlying condition of the patient. A healthy young patient may have no symptoms at all with hematocrit 27–29%, whereas an older patient with heart disease may develop dyspnea or anginal symptoms with the same hematocrit.
Diagnosis. Once a diagnosis of anemia is determined based on a low hematocrit or hemoglo- bin, the first step is to determine the MCV. Iron studies, reticulocyte count, peripheral smear, red cell distribution width (RDW), Coombs test, vitamin B12, folate level, and even a possible bone marrow biopsy may be necessary to determine a specific etiology.
Treatment. Besides blood transfusion, treatment cannot be generalized. Packed RBCs are used to maintain a hematocrit >25–30%. This is based on the underlying condition of the patient. A healthy young patient can have transfusion withheld until hematocrit is in the low 20%. An older patient with coronary artery disease will need to be maintained when hematocrit >30%. Hematocrit should rise approximately 3 points for every unit of packed RBCs given. Whole blood is rarely, if ever, used.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
194
MCV 80−100
Check Reticulocyte Count
MCV >100
Anemia
Hct <41% ♂ <36% ♀
Hb <13.5 g/dL ♂ <12 g/dL ♀
MCV <80
Macrocytic Anemia
Reticulocytosis (acute hemolysis)
Alcoholism
Drugs (AZT, phenytoin)
Megaloblastic Anemia
Macrocytosis + hypersegmented neutrophils
Folic acid deficiency
Vitamin B12 deficiency
Microcytic Anemia
Iron deficiency anemia
Anemia of chronic disease
Sideroblastic anemia
Thalassemia trait
Check MCV
Chapter 6 ● Hematology
Reticulocyte Count <3% (bad bone marrow response)
Reticulocyte Count >3% (good bone marrow response)
Aplastic anemia
Chronic renal failure
HUS
DIC
Macrovascular
Aortic stenosis
Prosthetic valves
Infection
Malaria
Babesia
Complement
Paroxysmal nocturnal hemoglobinuria
Enzyme
G6PD (severe type B)
Autoimmune: warm agglutinin disease (IgG Ab)
SLE
CLL
HIV
Membrane defect
Hereditary spherocytosis
Abnormal Hb
Sickle cell anemia
HbS and HbC
Enzyme
G6PD deficiency
Pyruvate kinase deficiency
Extravascular Hemolysis
• Jaundice
• Increased unconjugated bilirubin
• Pigment stones
Figure 6-1. Evaluation of Patients with Anemia
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
195
USMLE Step 2 l Internal Medicine
Clinical Pearl
In early iron deficiency, serum iron may be normal. (Ferritin is low and TIBC is elevated.)
MICROCYTIC ANEMIA
Iron Deficiency Anemia
Iron deficiency anemia is anemia with diminished RBC production and MCV <80, character- ized by hypochromic cells and low levels of stored iron. It is almost always caused by blood loss, most commonly GI or menstrual.
Iron absorption is tightly regulated. A man requires 1 mg per day and a woman 2–3 mg per day on average. It is difficult for the body to increase the level of iron absorption. If there is even a modest increase in blood loss—occult blood in the stool, heavier menstrual flow, or increased demand such as in pregnancy—the body is poorly equipped to increase its level of absorption to exceed 3–4 mg per day. Other etiologies are increased urinary loss of blood, mal- absorption, hemolysis, and poor oral intake.
Clinical Presentation. Mild anemia may have no or very limited symptoms. As hematocrit approaches 30%, fatigue and poor exercise tolerance may develop. As hematocrit lowers to 25%, tachycardia, palpitations, dyspnea on exertion, and pallor develop. Older patients and those with coronary artery disease may become dyspneic at higher levels of hematocrit. More severe anemia results in lightheadedness, confusion, syncope, and chest pain. A systolic ejection murmur (“flow” murmur) may develop in any patient with moderately severe anemia. These symptoms are not specific for iron deficiency anemia and may develop with any form of anemia provided it is sufficiently severe.
Symptoms specific to iron deficiency are rare and cannot be relied upon to determine the diagnosis: brittle nails, spoon-shaped nails, glossitis, and pica. Iron deficiency anemia as a specific diagnosis is determined by laboratory findings, not symptoms.
Diagnosis. A low serum ferritin <10 ng/mL is the most characteristic finding of iron deficien- cy anemia. Low ferritin has good specificity (>99%) but poor sensitivity (60%); the ferritin level may be falsely elevated because it is an acute phase reactant and may be elevated in other inflammatory states or with malignancy. MCV is low except in very early cases. The serum iron is low and the total iron binding capacity is high. The RDW is elevated. The most specific test, although rarely necessary, is a bone marrow biopsy looking for stainable iron stores. The reticulocyte count is low. Platelet levels rise.
Treatment. Treatment usually includes oral therapy with ferrous sulfate tablets, continued until Hb and Ht have normalized and an additional 2-3 months to “restore” iron stores. With replacement of iron, a brisk increase in reticulocytes will be seen 2 weeks into treatment. Parenteral iron is used in patients with malabsorption, kidney disease, or an intolerance to oral therapy. Blood transfusion is the most effective way to deliver iron but is reserved for those with severe symptoms.
Anemia of Chronic Disease
Anemia of chronic disease is a defect in the body’s ability to make use of iron sequestered in stores within the reticuloendothelial system. It can be microcytic or normocytic. Anemia can accompany virtually any chronic inflammatory, infectious, or neoplastic condition. Hepcidin, a regulator of iron metabolism, plays an important role in anemia of chronic disease. In states where hepcidin level is abnormally high (e.g., inflammation), serum iron falls due to iron trap- ping within macrophages and liver cells and decreased gut iron absorption. This typically leads to anemia caused by an inadequate amount of serum iron being available for developing red cells.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
196
Chapter 6 ● Hematology
Hepcidin inhibits iron transport by binding to the iron export channel ferroportin located on the surface of gut enterocytes and the plasma membrane of macrophages.
By inhibiting ferroportin, it prevents iron from being exported and the iron is seques- tered in the cells. It also prevents enterocytes from allowing iron into the hepatic portal system, thereby reducing dietary iron absorption.
The iron release from macrophages is also reduced by ferroportin inhibition.
In genetic diseases where hepcidin level is abnormally low, iron overload may occur (hemochromatosis) due to unwarranted ferroportin facilitated iron influx.
Clinical Presentation. Symptoms are based on the severity of the anemia. The only other symptoms are based on the specifics of the underlying disease.
Diagnosis. Serum ferritin level is normal or elevated. Serum iron level and total iron binding capacity (TIBC) are both low. Reticulocyte count is low.
Treatment. Correct the underlying disease. Iron supplementation and erythropoietin will not help, except in renal disease and anemia caused by chemotherapy or radiation therapy.
Sideroblastic anemia is a microcytic anemia caused by a disorder in the synthesis of hemoglobin, characterized by trapped iron in the mitochondria of nucleated RBCs. There are both hereditary and acquired forms. The hereditary form is due to a defect in aminolevulinic acid synthase or an abnormality in vitamin B6 metabolism. The acquired form is due to drugs such as chloram- phenicol, isoniazid, or alcohol. Lead poisoning can cause sideroblastic anemia as well.
There is an association with myelodysplastic syndromes and refractory anemia. Sideroblastic anemia may progress to acute myelogenous leukemia in a small percentage of patients.
Clinical Presentation. Symptoms are related to the severity of the anemia. There is no specific finding that will be sufficiently suggestive of sideroblastic anemia to allow a diagnosis without significant lab evaluation.
Diagnosis. Serum ferritin level is elevated. Transferrin saturation is very high, and thus TIBC is very low. Serum iron level is high. The most specific test is a Prussian Blue stain of RBCs in the marrow that will reveal the ringed sideroblasts. Marrow reticuloendothelial iron is strikingly increased. Sideroblastic anemia is the only microcytic anemia in which serum iron is elevated.
Treatment. Remove the offending drug. Some patients, especially those with INH-associated sideroblastic anemia, will respond to pyridoxine therapy 2-4 mg per day. Consider transfusion for serious cases and BMT for refractory cases.
Clinical Pearl
Both iron deficiency and anemia of chronic disease may have decreased serum iron.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
197
USMLE Step 2 l Internal Medicine
Copyright 2007 Gold Standard Multimedia Inc.
Figure 6-2. Basophilic Stippling, a Feature of Lead Poisoning and Other Diseases
Thalassemia is a hereditary underproduction of either the alpha or beta globin chains of the hemoglobin molecule, resulting in a hypochromic, microcytic anemia. Gene deletion results in variable levels of disease. There are 4 genes coding for the alpha chain of hemoglobin.
There can be deletions of 1, 2, 3, or all 4 genes.
Alpha thalassemia is more common in Asian populations, while beta thalassemia is more common in Mediterranean populations.
Clinical Presentation. Presentation depends on the number of abnormal genes.
1 gene deletion yields a normal patient; CBC, hemoglobin, and MCV are normal.
2 gene deletion yields a mild anemia with hematocrit 30–40% and strikingly low MCV.
3 gene deletion yields a more profound anemia with hematocrit 22–32% and very low MCV.
4 gene deletion alpha thalassemia causes patients to die in utero, secondary to gamma chain tetrads called hemoglobin Barts.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
198
Chapter 6 ● Hematology
In beta thalassemia trait there is a mild anemia with marked microcytosis (low MCV).
– Patients with beta thalassemia major (or Cooley’s anemia) are homozygous for mutations of both genes coding for the beta hemoglobin gene. Patients become severely symptomatic starting age 6 months, when the body would normally switch from fetal hemoglobin to adult hemoglobin. They are severely symptomatic with growth failure, hepatosplenomegaly, jaundice, and bony deformities secondary to extramedullary hematopoiesis. They are later symptomatic from hemochromatosis, cirrhosis, and CHF from chronic anemia and transfusion dependence.
Diagnosis. Clues to the diagnosis of thalassemia trait is a mild anemia with a profound microcytosis. Beta thalassemia major has the severe symptoms, large spleen, and bone abnormalities described. Both forms of thalassemia are diagnosed by having a microcytic anemia with normal iron studies. Hemoglobin electrophoresis differentiates which type of thalassemia is present. In beta thalassemia, there is an increased level of hemoglobin F and hemoglobin A2. In beta thalassemia major, the hemoglobin is as low as 3–4 g/dL. Those with
alpha thalassemia will have normal amounts of hemoglobins F and A2. Tetrads of beta chains
are called hemoglobin H. Hemoglobin H is present in alpha thalassemia with 3 of 4 genes
deleted. Target cells are present in all forms of thalassemia trait and thalassemia major. The RDW is normal in all forms because all of the cells are of the same size.
Treatment. Thalassemia traits of both the alpha and beta types do not require specific treat- ment. Beta thalassemia major patients require blood transfusions once or twice a month. The chronic transfusions lead to iron overload, which requires treatment with deferasirox. Oral deferasirox is the standard of care. This is easier to give than deferoxamine, which requires a subcutaneous pump. Splenectomy eliminates a major area of hemolysis and therefore helps reduce transfusion requirements. A small number of patients can be treated with a bone marrow transplantation.
Table 6-1. Iron Indices in Microcytic Anemia Syndromes
Clinical Pearl Thalassemia trait syndromes are asymptomatic.
Fe Panel | ||||
Serum Iron | ||||
Serum Ferritin | Decreased or Normal (early) | |||
Transferrin/ TIBC | Increased | Decreased | Decreased | Normal |
% Saturation | Decreased | N/ Decreased | Increased | Normal |
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
199
USMLE Step 2 l Internal Medicine
Clinical Recall
Which of the following laboratory investigations has the highest specificity and sensitivity in the diagnosis of iron deficiency anemia?
Serum ferritin level
Serum iron level
Serum TIBC
Serum MCV
Bone marrow biopsy
Answer: E
Vitamin B12 (Cyanocobalamine) Deficiency
Vitamin B12 deficiency is decreased absorption or intake of vitamin B12, resulting in hematologic and/or neurologic abnormalities. The most common cause is pernicious anemia, a disorder causing decreased intrinsic factor production due to autoimmune destruction of parietal cells. The incidence of pernicious anemia increases with age. Gastrectomy and atrophic gastritis can also decrease intrinsic factor production. Various forms of malabsorption such as sprue, regional enteritis, and blind loop syndrome can block absorption of vitamin B12.
Pancreatic insufficiency can result in the inability to absorb the vitamin. Rarely, tapeworm infection with Diphyllobothrium latum can decrease absorption. Decreased intake is unusual and requires several years to produce disease.
Clinical Presentation. Manifestations vary with the severity of the anemia. As such, you cannot specifically determine that a patient has B12 deficiency only from the symptoms of anemia.
Neurologic manifestations may involve almost any level of the neurologic system. Patients may have peripheral neuropathy, position sense abnormality, vibratory, psychiatric, autonomic, motor, cranial nerve, bowel, bladder, and sexual dysfunction. Glossitis, diarrhea, and abdominal pain may occur. You may have either the hematologic or neurologic deficits individually or combined.
Diagnosis. Anemia with macrocytosis (increased MCV). A smaller number of patients may have the neurologic deficits alone. The WBCs have hypersegmented neutrophils with a mean lobe count >4. The red cells are characterized by macro-ovalocytes. Although macrocytosis can occur with hemolysis, liver disease, and myelodysplasia, these give round macrocytes. B12 and folate deficiency produce oval macrocytes. The hematologic pattern of vitamin B12 deficiency is indistinguishable from folate deficiency. The reticulocyte count is reduced, although the bone marrow is hypercellular. Pancytopenia may occur. An elevated LDH, bilirubin, and iron level may occur and are due to mild hemolysis of immature erythrocytes.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
200
Chapter 6 ● Hematology
The most specific test is a low B12 level. Antibodies to intrinsic factor and parietal cells confirm the etiology as pernicious anemia. The Schilling test is rarely used to determine the etiology of vitamin B12 deficiency. It is not necessary if the patient has a low B12 level com- bined with the presence of antibodies to intrinsic factor. An elevated methylmalonic acid level occurs with B12 deficiency and is useful if the B12 level is equivocal.
Treatment. Replace the vitamin B12 lifelong. Options available for treating clinical vitamin B12 deficiency include oral (daily) and parenteral (monthly intramuscular or subcutane- ous) preparations. Parenteral route is recommended for patients with neurologic manifesta- tions of B12 deficiency. IV dosing is not recommended because that would result in most of the vitamin being lost in the urine.
Response of vitamin B12 deficiency anemia to treatment is usually rapid, with reticulocytosis occurring within 2–5 days and hematocrit normalizing within weeks. Treatment with cobala- min effectively halts progression of the deficiency process but might not fully reverse more advanced neurologic effects. If the underlying cause of the vitamin B12 deficiency is treatable (e.g., fish tapeworm infection or bacterial overgrowth), then treatment should include address- ing the underlying etiology.
Patients who have vitamin B12 deficiency with associated megaloblastic anemia might experience severe hypokalemia and fluid overload early in treatment due to increased erythro- poiesis, cellular uptake of potassium, and increased blood volume. Once treated for a vitamin B12 deficiency due to pernicious anemia or other irreversible problems with absorption, patients need to continue some form of cobalamin therapy lifelong.
Folic acid replacement can correct the hematologic abnormalities of B12 deficiency, but not the neurologic abnormalities.
Folic Acid Deficiency
Folic acid deficiency is almost always caused by some form of decreased dietary intake. It can lead to anemia. Occasionally, increased requirements from pregnancy, skin loss in diseases like eczema, or increased loss from dialysis and certain anticonvulsants such as phenytoin may occur. Con- sumption of high amounts of alcohol may have a direct effect on the folate absorption, due to inhibition of the enzyme intestinal conjugase. Folate is presented in foods as polyglutamate, which is then converted into monoglutamates by intestinal conjugase.
Clinical Presentation. Presentation depends entirely on the severity of the anemia.
Diagnosis. The hematologic presentation of folic acid deficiency is identical to B12 deficiency. The diagnosis is based on a low red-blood-cell, folic-acid level.
Treatment. Replace folic acid, almost always orally.
HEMOLYTIC ANEMIA
Hemolytic anemias are caused by decreased RBC survival from increased destruction of the cells. The destruction may be inside the blood vessels (intravascular) or outside (extravascular), which generally means inside the spleen. Hemolytic anemia may be chronic (sickle cell disease, paroxys- mal nocturnal hemoglobinuria, and hereditary spherocytosis) or acute (drug-induced hemolysis, autoimmune hemolysis, or glucose 6-phosphate dehydrogenase deficiency).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
201
USMLE Step 2 l Internal Medicine
Table 6-2. Classification of Hemolytic Anemias
Hereditary Anemias | Acquired Anemias |
Membrane: hereditary spherocytosis, hereditary elliptocytosis | Immune
|
Metabolism: G6PD deficiency, pyruvate kinase deficiency | Red Cell Fragmentation Syndromes |
Infections: malaria, clostridia | |
Chemical and Physical Agents: drugs, indus- trial/domestic substances, burns | |
Secondary: liver and renal disease | |
Paroxysmal Nocturnal Hemoglobinuria |
Clinical Presentation. The usual symptoms of anemia are present based on the severity of the disease, not necessarily the etiology. Fatigue and weakness occur with mild disease. Dyspnea and later confusion occur with more severe disease. The major difference between hemolytic anemia and the micro- and macrocytic anemias is that hemolysis is more often the etiology when the onset is sudden. This is, of course, provided that simple blood loss has been exclud- ed. Hemolysis is often associated with jaundice and dark urine as well. Specific findings associated with each disease are described below. Fever, chills, chest pain, tachycardia, and backache may occur if the intravascular hemolysis is particularly rapid.
Diagnosis. Patients with hemolytic anemias generally have a normal MCV, but the MCV may be slightly elevated because reticulocytes are somewhat larger than older cells. The reticulocyte count is elevated. The LDH and indirect bilirubin are elevated. Bilirubin levels above 4 are unusual with hemolysis alone. The peripheral smear may aid in the specific diagnosis, and the haptoglobin may be low with intravascular hemolysis. Hemoglobin may be present in the urine when intravascular hemolysis is sudden and severe because free hemoglobin spills into the urine. There should not be bilirubin in the urine because indirect bilirubin is bound to albumin and should not filter through the glomerulus. Hemosiderin is a metabolic product of hemoglobin. Hemosiderin may be present in the urine if the hemolysis is severe and lasts for several days.
Treatment. Transfusion is needed as in all forms of anemia when the hematocrit becomes low. Hydration is, in general, useful to help prevent toxicity to the kidney tubule from the free hemo- globin. Specific therapy is discussed with each disease below. Patients with chronic hemolytic anemia need to be maintained on chronic folic acid therapy, as there is an increase in cell turnover.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
202
Chapter 6 ● Hematology
Sickle Cell Disease
Sickle cell disease is a hereditary form of chronic hemolysis, ranging from asymptomatic to severe, overwhelming crisis. It is characterized by irreversibly sickled cells and recurrent painful crises.
Autosomal recessive hereditary disease
Hemoglobin S is due to a substitution of a valine for glutamic acid as the sixth amino acid of the beta globin chain.
Heterozygous form (trait) (8% of African-Americans); all those with the trait are asymptomatic
Homozygous form (disease) (1 in 400 African-Americans)
A sickle cell acute painful crisis may be precipitated by hypoxia, dehydration, acidosis, infection, and fever. However, the crisis may occur without the presence of these factors.
Sickle cell crisis is usually not associated with an increase in hemolysis or drop in hematocrit.
If increased hemolysis occurs, consider another etiology such as concomitant glucose 6 phosphate dehydrogenase deficiency (G6PD) or acute splenic sequestra- tion in a child.
If a sudden drop in hematocrit occurs, consider another etiology such as Parvovi- rus B19 infection or folate deficiency. The drop in hematocrit is from acute aplasia (decrease in cell production), not from hemolysis.
Clinical Presentation. Chronic manifestations include renal concentrating defects (isosthenuria), hematuria, ulcerations of the skin of the legs, bilirubin gallstones, aseptic necrosis of the femoral head, osteomyelitis, retinopathy, recurrent infections from Pneumococ- cus or Haemophilus, growth retardation, and splenomegaly followed in adulthood by autosple- nectomy. The acute painful crisis consists of back, rib, chest, and leg pain. Occasionally some patients will have very severe and life-threatening manifestations of sickling. These include the acute chest syndrome consisting of severe chest pain, fever, leukocytosis, hypoxia, and infil- trates on the chest x-ray. The acute chest syndrome is indistinguishable from pneumonia.
Stroke and TIA may also occur. Priapism can occur from infarction of the prostatic plexus of veins. Blindness and even myocardial infarction and cardiomyopathy may also occur. Pregnant patients experience increased rates of spontaneous abortion and low birth weight.
Sickle trait gives normal hematologic picture with no anemia and a normal MCV. The only significant manifestation of trait is the renal concentrating defect presenting with isosthenuria and microscopic hematuria. Sickle trait also increases the frequency of UTI. Those with trait will rarely develop the acute pain crisis under conditions of profound hypoxia and acidosis.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
203
USMLE Step 2 l Internal Medicine
Copyright 2007 Gold Standard Multimedia Inc.
Figure 6-3. Sickle Cells Noted on a Peripheral Blood Smear
Diagnosis. Patients with sickle cell disease typically have a mild to moderate anemia with a normal MCV. The reticulocyte count should always be elevated in the 10–20% range unless they have folate deficiency or Parvovirus B19 aplastic crisis. LDH and bilirubin are elevated as
in all types of hemolytic anemias. The hemoglobin electrophoresis is the most specific test. The
peripheral smear shows sickled cells. The sickle prep (or Sickledex) is a quick screening test used to diagnose evidence of sickle cell trait and cannot distinguish between trait and homozy- gous disease. The urinalysis usually has blood present, although it is often microscopic. The white blood cell count is often elevated in the 10,000–20,000 range, although this can also indicate the presence of infection.
Treatment. An acute sickle cell pain crisis is treated with fluids, analgesics, and oxygen. Antibiotics are given with infection or even to patients with fever and leukocytosis even if a definite site of infection has not been documented. Ceftriaxone is the preferred agent because it covers Pneumococcus and Haemophilus influenza. Severe or life-threatening manifestations such as acute chest syndrome, CNS manifestations, priapism, and acute cardiac manifestations are managed with red blood cell transfusions if the hematocrit is low, and exchange transfusion if the hematocrit is high. Chronic management includes folic acid replacement and vaccinations against Pneumococcus and influenza. Hydroxyurea is used to decrease the frequency of the
vaso-occlusive pain crisis. Bone marrow transplantation can be curative in severe cases.
Autoimmune, Cold Agglutinin, and Drug-Induced Hemolytic Anemia
Various forms of acquired hemolytic anemias can result from the production of IgG, IgM, or activation of complement C3 against the red cell membrane. They are often sudden and idiopathic. The lysis can be intravascular or extravascular (far more common). That is because
the destruction of the cells most often occurs through macrophages in the spleen or by Kupffer cells in the liver.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
204
Chapter 6 ● Hematology
Autoimmune destruction is often idiopathic. Known causes of autoimmune destruction are from antibodies produced in relationship to various forms of leukemia, especially chronic lymphocytic leukemia, viral infections, lymphoma, collagen vascular diseases like lupus, or in relationship to drugs. The most common drugs are the penicillins, cephalosporins, sulfa drugs, quinidine, alpha-methyldopa, procainamide, rifampin, and thiazides.
Ulcerative colitis can also lead to autoimmune hemolytic anemia. Cold agglutinin disease is an IgM antibody produced against the red cell in association with malignancies such as lymphoma or Waldenstrom macroglobulinemia and infections such as Mycoplasma or mononucleosis. Cold agglutinin destruction occurs predominantly in the liver. Liver-mediated destruction is not affected by steroids. Up to 50% of patients do not have an associated underlying disorder.
Clinical Presentation. Symptoms are generally related to the severity of the anemia, not the etiology. The onset may be very sudden resulting in fever, syncope, congestive failure, and hemoglobinuria. Mild splenomegaly is present when the disease has been occurring long enough for the time it takes for the spleen to enlarge. The drug history is often the clue with drug-induced varieties. Cold agglutinin disease results in cyanosis of the ears, nose, fingers, and toes. Weakness, pallor, jaundice, and dark urine may occur as it can in all forms of hemolysis of sufficient severity.
Diagnosis. Autoimmune hemolysis gives a normocytic anemia, reticulocytosis, increased LDH, absent or decreased haptoglobin, and increased indirect bilirubin, as can all forms of hemolysis. The Coombs test is the specific test that diagnoses autoimmune, cold agglutinin, and often even drug-induced hemolysis. Spherocytes are often present on the smear.
Copyright 2007 Gold Standard Multimedia Inc.
Figure 6-4. Acanthocytes, a Feature of Several Hematologic and Systemic Diseases
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
205
USMLE Step 2 l Internal Medicine
Treatment. Mild disease often occurs, which needs no treatment. In cases of drug-induced hemolysis, stop the offending drug. More severe autoimmune hemolysis is treated with steroids first. Splenectomy is done for those unresponsive to steroids. Cold agglutinin disease is primar- ily managed by avoiding the cold. Most cases of cold agglutinin disease are mild, but in those who have severe disease despite conservative measures, azathioprine, cyclosporine, or cyclo- phosphamide can be used. Rituximab is also useful. This is an anti-CD20 antibody. Steroids and splenectomy don’t work well with cold agglutinin disease because the destruction occurs in the liver. You need to control the lymphocytes which control the production of IgM.
Hereditary Spherocytosis
Hereditary spherocytosis is a chronic mild hemolysis with spherocytes, jaundice, and spleno- megaly from a defect in the red cell membrane. It is an autosomal dominant disorder where the loss of spectrin in the red cell membrane causes the red cell to form as a sphere, rather than as a more flexible and durable biconcave disc. Hemolysis occurs because the spheres are not able to pass the narrow passages in the spleen.
Clinical Presentation. A chronic disorder with mild to moderate symptoms of anemia. Because the hemolysis occurs in the spleen, there is often splenomegaly and jaundice. Severe anemia occasionally occurs from folate deficiency or Parvovirus B19 infection such as in sickle
cell disease. Bilirubin stones often occur, leading to cholelithiasis, often at a young age.
Diagnosis. A normal to slightly decreased MCV anemia with the elevated LDH; indirect bilirubin and reticulocyte count similar to any kind of hemolysis. Although spherocytes may be present with autoimmune hemolysis, hereditary spherocytosis has a negative Coombs test. The cells have increased sensitivity to lysis in hypotonic solutions known as an osmotic fragility test. The mean corpuscular hemoglobin concentration (MCHC) is elevated.
Treatment. Most patients require no treatment beyond folate replacement chronically. In those with more severe anemia, removal of the spleen will eliminate the site of the hemolysis. The symptoms and jaundice will resolve but the spherocytes will remain.
Copyright 2007 Gold Standard Multimedia Inc.
Figure 6-5. Features of Hereditary Spherocytosis Seen on Peripheral Blood Smear
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
206
Chapter 6 ● Hematology
Paroxysmal Nocturnal Hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a red cell membrane defect leading to intermittent dark urine and venous thrombosis and a chronic form of hemolysis. A red cell membrane defect in phosphatidyl-inositol glycan A (PIG-A) allows increased binding of complement to the red cell, leading to increased intravascular hemolysis. It is a clonal stem-cell disorder, and so can develop into aplastic anemia and leukemia. The cells are more susceptible to lysis by complement in an acid environment. Everyone becomes a little acidotic at night because of a relative hypoventilation.
Clinical Presentation. In addition to symptoms of anemia, these patients characteristically present with dark urine from intravascular hemolysis. Thrombosis of major venous structures, particularly the hepatic vein (Budd-Chiari syndrome), is a common cause of death in these patients. The hemoglobinuria is most commonly in the first morning urine because the hemolysis occurs more often when patients develop a mild acidosis at night.
Diagnosis. Besides the usual lab findings of hemolysis, such as an increased LDH, bilirubin, and reticulocyte count, these patients have brisk intravascular hemolysis and therefore have a low haptoglobin and hemoglobin in the urine. Hemosiderinuria occurs when the capacity of renal tubular cells to absorb and metabolize the hemoglobin is overwhelmed, and the sloughed off iron-laden cells are found in the urine. The gold standard test is flow cytometry for CD55 and CD59 on white and red cells. In PNH, levels are low or absent.
Treatment. Treatment for PNH depends on the severity of symptoms. Some patients with few or no symptoms require only folic acid and possible iron supplementation. Over time, the dis- ease may progress and thus require more aggressive care.
In the anemic patient with signs of hemolysis, prednisone is often given to slow the rate of red blood cell destruction.
In the patient with acute thrombosis, thrombolytic therapy (streptokinase, urokinase, or tissue plasminogen activator) is often administered, followed by long-term antico- agulation drugs to help prevent further blood clots.
Antiplatelet agents such as aspirin and ibuprofen may also help prevent blood clots. Unfortunately, some patients will continue to develop blot clots despite aggressive anti-coagulation agents.
Avoid medications that increase the risk for thrombosis, such as oral birth control pills.
PNH is often associated with bone marrow failure. Occasionally patients will respond to antithymocyte globulin, but frequently they will continue to require red cell and/or platelet transfusions. Allogeneic bone marrow transplantation has been the mainstay of curative therapy for PNH. Recently, the drug eculizumab (brand name Soliris) was approved by the FDA to treat symptoms of the disease.
Glucose-6-Phosphate Dehydrogenase Deficiency
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a hereditary deficiency of an enzyme for producing the reducing capacity necessary for neutralizing oxidant stress to the red cell resulting in acute hemolysis.
Various forms of oxidant stress result in sudden hemolysis. The most common type of oxidant stress is actually from infections, not drugs. The most commonly implicated drugs are sulfa drugs, primaquine, dapsone, quinidine, and nitrofurantoin.
Note
Decay accelerating factor (DAF) is also known as CD55 and CD59. DAF are the main proteins that protect RBCs from complement destruction.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
207
USMLE Step 2 l Internal Medicine
Clinical Presentation. Patients are normal until exposed to the stress. A sudden, severe, intravascular hemolysis can occur including jaundice, dark urine, weakness, and tachycardia. The history of recent drug ingestion is the main clue to the diagnosis.
Diagnosis. The usual findings of an intravascular hemolysis include high LDH, bilirubin, and reticulocyte count with a normal MCV, low haptoglobin, and hemoglobinuria. Heinz bodies are precipitated hemoglobin inclusions seen in red cells. Bite cells are seen on smear indicat- ing the removal of the Heinz bodies. The definitive test is the G6PD level, which can be falsely normal immediately after an episode of hemolysis. Hence, the level is best tested about 1 week after the event.
Treatment. There is no specific therapy beyond hydration and transfusion if the hemolysis is severe. The main therapy is to avoid oxidant stress in the future.
Answer: D
Aplastic anemia is failure of all 3 cell lines produced in the bone marrow, resulting in anemia, leukopenia, and thrombocytopenia (pancytopenia). The marrow is essentially empty with the absence of precursor cells. Many things can cause bone marrow failure, but the most common cause of true aplastic anemia is not often determined. Radiation, toxins such as benzene, drugs such as NSAIDs, chloramphenicol, alcohol, and chemotherapeutic alkylating agents can all cause aplastic anemia. Infiltration of the marrow with infections such as tuberculosis or cancer such as lymphoma can cause pancytopenia, but that is not truly aplastic anemia. Aplastic anemia can also be caused by infections such as hepatitis, HIV, CMV, Epstein-Barr virus, or Parvovirus B19 in immunocompromised patients.
Clinical Presentation. Patients typically present with bleeding from the thrombocytopenia, and possibly with a combination of the findings associated with deficiencies in all 3 cell lines. Fatigue from anemia and infections from neutropenia may also occur. The clinical presenta- tion may give a clue to the presence of pancytopenia but is not sufficient to determine a true aplastic anemia by clinical manifestations alone. The absence of a classical association such as benzene, radiation, or chloramphenicol would most certainly not exclude a diagnosis of aplastic anemia. The most common single etiology is idiopathic.
Diagnosis. Pancytopenia on a CBC is the first test. A bone marrow biopsy confirms the diagno- sis when alternative etiologies for a pancytopenia are not present. In other words, the marrow is
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
208
Chapter 6 ● Hematology
empty of almost all precursor cells as well as evidence of primary or metastatic cancer, infection, or fibrosis. The marrow is hypoplastic and fat filled with no abnormal cells seen.
Treatment. Treatment includes bone marrow transplant when the patient is young and healthy enough to withstand the procedure and there is a donor available (cure rate is 80–90% of patients age <50).
When bone marrow transplant is not possible, try immunosuppressive agents: a combination of antithymocyte globulin, cyclosporine, and prednisone (can lead to remission in 60–70% of patients). It is believed that T lymphocytes are primarily causal in the bone marrow failure, so drugs are used to decrease the T-cell response.
ACUTE LEUKEMIA
Acute leukemia is the rapid onset of bone marrow failure from the derangement of the pluripotent stem cell, causing the relentless destruction of the normal production of the entire bone marrow. Blood cells lose their ability to mature and function normally. Most cases of acute leukemia arise with no apparent cause, but there are several well known associations: radiation exposure, benzene, chemotherapeutic agents such as melphalan and etoposide, and some retroviruses.
Genetic disorders such as Down syndrome and Klinefelter can cause an increased incidence of leukemia. Myelodysplasia and sideroblastic anemia can also develop into acute leukemia.
Clinical Presentation. Patients typically present with the effects of the leukemic blast cells crowding out the normal marrow cells, leading to symptoms of bone marrow failure (even if total WBC count is elevated or normal). Fatigue from anemia is the most common presenting complaint. Bleeding from thrombocytopenia occurs. Infection from the underproduction or abnormal function of WBCs also occurs.
Acute lymphocytic leukemia (ALL) is more common in children and acute myelogenous leukemia (AML) is more common in adults, but they are indistinguishable clinically. ALL is more often associated with infiltration of other organs, but AML can do it as well. Enlargement of the liver, spleen, and lymph nodes and bone pain are common at presentation. Disseminated intravascular coagulation (DIC) is associated with M3 promyelocytic leukemia. CNS involvement resembling meningitis is present at the time of initial diagnosis in about 5% of patients. CNS involvement is most characteristic of M4 and M5 monocytic leukemia. Rarely, a syndrome of “leukostasis” can occur when the white cell count is extremely elevated. This results from sludging of the leukemic cell in the vasculature, resulting in headache, dyspnea, confusion, and brain hemorrhage.
Diagnosis. The CBC is the first clue to the diagnosis. Most commonly, WBC is elevated, along with thrombocytopenia and anemia. In about 10% of acute leukemias, depression of all 3 cell lines is evident (aleukemic leukemia). Many other disorders can present as pancytopenia similar to leukemia such as aplastic anemia, infections involving the marrow, metastatic cancer involving the marrow, vitamin B12 deficiency, SLE, hypersplenism, and myelofibrosis. None of these will have leukemic blasts circulating in the peripheral blood, however. A bone marrow biopsy showing >20% blasts confirms the diagnosis of acute leukemia. The presence of blasts tells you the patient has acute leukemia, but blast analysis cannot be relied upon to always tell which type is present. AML is characterized by the presence of Auer rods, myeloperoxidase, and esterase. ALL is characterized by the presence of the common ALL antigen (CALLA) and terminal deoxynucleotidyl transferase (TdT). Auer rods are most specific for M3. Ultimately, the diagnosis rests upon the use of monoclonal antibodies, which recognize specific types of leukemia as well as the expression of specific CD antigens on the surfaces of the cells. Nonspe- cific findings that are also present are hyperuricemia and an increased level of LDH.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
209
USMLE Step 2 l Internal Medicine
Note
CML can be confused with a leukemoid reaction. They are distinguishable based upon the leukocyte alkaline phosphatase score.
Treatment. Chemotherapy is used initially in all patients to induce a remission. Inducing a remission means a removal of over 99.9% of the leukemic cells in the body and the elimination of peripheral blasts in circulation. This is followed by further rounds of chemotherapy to “consoli- date” the leukemia further. After chemotherapy, adults with AML or ALL should be referred for allogeneic bone marrow transplantation. The initial chemotherapy for AML is cytosine arabino- side (AraC) and either daunorubicin or idarubicin. The initial chemotherapy for ALL is dauno- rubicin, vincristine, and prednisone. Promyelocytic leukemia is managed with the addition of the vitamin A derivative all-trans-retinoic acid (ATRA). Leukostasis events are managed with leukapheresis in addition to the chemotherapy.
ALL patients must also undergo prophylaxis of the central nervous system to prevent relapse there. The best agent for this is intrathecal methotrexate.
Chronic myelogenous leukemia (CML) is a chronic myeloproliferative disorder characterized by the massive overproduction of myeloid cells. The cells retain most of their function until later in the course of the disease. Although the Philadelphia chromosome is characteristic of the disease, the cause of the production of this chromosome is unknown. It is a clonal disorder of myelocytes. The Philadelphia chromosome is a translocation between chromosomes 9 and 22, resulting in a gene producing an enzyme with tyrosine kinase activity.
Five percent of cases are Philadelphia-chromosome-negative.
Clinical Presentation. A markedly elevated white blood cell count can be found on routine blood count. The most common symptoms are fatigue, night sweats, and low-grade fever. Abdominal pain from massive enlargement of the spleen is common. Bone pain from infiltra- tion with white cells can occur. Enlarged lymph nodes are rare. Infection and bleeding are uncommon because these white cells retain the majority of their function. Rarely, a leukostasis reaction can occur from extremely elevated amounts of white cells being produced in the range of 200,000–500,000/mm3.
The white cells then clog up the vasculature, resulting in dyspnea, blurry vision, priapism, thrombosis, and stroke.
Diagnosis. The main feature of the disease is an elevated white blood cell count consisting predominantly of neutrophils with a left shift. Blasts are either absent or present in very small amounts (<5%). The leukocyte alkaline phosphatase score (LAP) is diminished. Basophilia is characteristic of CML and all myeloproliferative disorders such as polycythemia vera.
Although the B12 level is often elevated, this would not be enough to establish the diagnosis. The Philadelphia chromosome is a far more specific test for CML and should be done in a patient with a markedly elevated white cell count. A low LAP score is not as important as the PCR for Bcr/Abl. The platelet count can also be markedly elevated.
Treatment. The best initial therapy for CML is imatinib, which is also known by the manu- facturer’s name, Gleevec®. Imatinib is a direct inhibitor of the tyrosine kinase produced by the Philadelphia chromosome. There is nearly a 90% hematologic response to imatinib, and as many as 60 to 70% of patients may lose the Philadelphia chromosome. The milder the disease, the greater the degree of hematologic response. Bone marrow transplantation is no longer the
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
210
Chapter 6 ● Hematology
clear first choice as therapy for CML. This is because of the extraordinary response to imatinib, as well as the high mortality associated with the bone marrow transplantation itself. If imatinib fails, then the therapy is bone marrow transplantation.
Chronic Lymphocytic Leukemia (CLL)
Chronic lymphocytic leukemia (CLL) is a massive overproduction of mature—but still leukemic— lymphocytes, usually from the monoclonal production of B lymphocytes. Etiology is unknown.
Clinical Presentation. CLL can often present as an asymptomatic elevation of white cells found on routine evaluation of patients or during investigations for other problems. Patients are exclusively older with 90% being age >50. When patients do have symptoms, they are often nonspecific—fatigue, lethargy, and uncomfortable enlargement of lymph nodes.
Infiltration of other parts of the reticuloendothelial system such as the spleen, liver, and bone marrow also occurs. Infection and bleeding are unusual presentations of the disease. Staging for CLL is as follows:
Stage 0: lymphocytosis alone
Stage 1: lymphadenopathy
Stage 2: splenomegaly
Stage 3: anemia
Stage 4: thrombocytopenia
Staging is important because the survival of untreated stage 0 and stage 1 disease is 10–12 years even without treatment. The survival of stage 3 and stage 4 disease is 1–2 years. CLL can be associated with various autoimmune phenomena such as thrombocytopenia and autoim- mune hemolytic anemia.
Diagnosis. CLL is strongly suspected when an older patient has a marked elevation in the white cell count with a marked lymphocytic predominance in the range of 80–98% lymphocytes. The marrow is often infiltrated with the leukemic lymphocytes. CD19 is an antigen strongly associated with CLL. The cell count is usually elevated in the range of 30,000–50,000, but may go as high as 150,000. “Smudge cells” seen on a smear are characteristic of CLL.
Treatment. Early stage CLL with only an elevated white cell count or enlargement of lymph nodes is not treated. However, patients with symptomatic disease always need to be treated. Those with more advanced-stage disease should receive initial therapy with fludarabine.
Fludarabine has greater efficacy than chlorambucil and should be considered the drug of choice. Autoimmune hemolysis and thrombocytopenia are treated with prednisone. Rituximab is used in those patients who express CD20, especially with autoimmune ITP or hemolytic anemias.
Hairy cell leukemia (HCL), a subtype of CLL, makes up 2% of all leukemias. It is character- ized by an accumulation of abnormal B lymphocytes. The malignant B lymphocytes (“hairy cells” ) accumulate in the bone marrow, interfering with the production of normal cells com- monly causing pancytopenia. Patients develop infections, anemia and fatigue, or easy bleed- ing. Early satiety may occur from massive splenomegaly.
HCL is commonly considered in the differential diagnosis after routine blood count shows unexpectedly low numbers of cell lines or after unexplained bruising or recurrent infections in an otherwise apparently healthy patient.
Bone marrow biopsy is necessary for final diagnosis: the biopsy is used to confirm both the presence of HCL and the absence of any additional diseases.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
211
USMLE Step 2 l Internal Medicine
Diagnosis can be confirmed by viewing the cells with a special stain known as TRAP (tartrate resistant acid phosphatase).
Pancytopenia in HCL is caused primarily by marrow failure and splenomegaly. Bone marrow failure is caused by the accumulation of hairy cells and reticulin fibrosis in the bone marrow, as well as by the unfavorable effects of dysregulated cytokine production.
For treatment, purine analogs cladribine (2CDA) and pentostatin are the most common first-line therapies. For cladribine-resistant disease, consider monoclonal antibodies (rituximab most common) which destroy the malignant B cells. Alpha interferon is helpful in 60% of patients to stabilize the disease or produce a slow, minor improvement. More than 95% of new patients are treated well or at least adequately by cladribine or pentostatin; most can expect a disease-free remission time span of 10 years or even longer after taking one of these drugs just once.
Myelodysplastic Syndrome (MDS)
MDS is an idiopathic disorder that is considered “pre-leukemic,” in that a number of people go on to develop acute myelogenous leukemia (AML). MDS is probably from a genetic defect.
The most common defect is 5q deletion or “5q–.” Patients are usually elderly and present with a pancytopenia, elevated MCV, fatigue, infections, and/or bleeding because of the low cell counts. There is a small number of blasts from 1–20% and, in fact, it is the percentage of blasts present that tells how “close” a person is to AML.
Most patients die of infection or bleeding before they develop AML. This is because the disorder is slowly progressive and older patients “wear out” so to speak from cytopenias, more often than not going into the “blast phase” that characterizes AML. By definition, you must exclude B12 and folate deficiency because the disorder is so similar.
CBC and bone marrow are indispensable. You may find a bi-lobed neutrophil called a Pelger-Huet cell which is characteristic. Genetic testing for the 5q– is essential.
Treatment is periodic transfusions and control of the infections as they arise. Disease-specific therapy consists of the TNF inhibitor lenalidomide or thalidomide. Azacitidine or decitabine is useful when the 5q- is present. Some patients who are young enough with a match can undergo bone marrow transplantation.
Polycythemia Vera
Polycythemia vera is a disorder of red cell production. Red cells are produced in excessive amounts in the absence of hypoxia or increased erythropoietin levels.
Clinical Presentation. Patients present with:
Markedly elevated hematocrit
Splenomegaly
Sometimes elevation of the platelet and white cell counts
Thrombosis
“Plethora” or redness and fullness of the face
Pruritis (approximately 40% of patients), particularly after exposure to warm water such as in a shower or bath; possibly caused by abnormal histamine or prostaglandin production
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
212
Chapter 6 ● Hematology
Diagnosis. Diagnose with a high hematocrit in the absence of hypoxia, carbon monoxide poisoning, or elevated erythropoietin level. The most specific test is the Janus Kinase or JAK-2.
Treatment: Phlebotomy is the primary treatment; hydroxyurea may be used in addition to or as an alternative. Aspirin is used to reduce the risk of thrombotic events.
Essential Thrombocythemia
Essential thrombocythemia is a type of platelet cancer. Platelet count may be over a million. There is either thrombosis or bleeding. The most specific test is JAK-2. Treat with hydroxyurea and sometimes anagrelide.
Clinical Recall
Observation
Fludarabine
Prednisone
Rituximab
PLASMA CELL DISORDERS
Multiple Myeloma
Multiple myeloma is a clonal abnormality of plasma cells resulting in their overproduction replacing the bone marrow as well as the production of large quantities of functionless immunoglobulins. The disease is characterized by various systemic manifestations such as bone, kidney, and infectious complications. Etiology is unknown.
Clinical Presentation. Bone pain is the most common clinical manifestation, usually in the back and the ribs, secondary to pathologic fractures. Radiculopathy from the compression of spinal nerve roots is also common. Infection particularly with encapsulated organisms such as Pneumococcus and Haemophilus is common. Renal failure and anemia are common. The symptoms of hypercalcemia such as polyuria, polydipsia, and altered mental status may occur. Weakness, fatigue, and pallor are common. Rarely, symptoms of a hyperviscosity syndrome such as blurry vision, confusion, and mucosal bleeding may occur.
Diagnosis. Although a normochromic, normocytic anemia is the most common laboratory finding, this is not specific for myeloma. A protein electrophoresis with a markedly elevated monoclonal immunoglobulin spike is present in almost all cases. This is most commonly IgG but may be IgA, IgD, or rarely a combination of two of these. In about 80% of individuals, routine x-ray will reveal the punched-out lytic lesion caused by the overproduction of osteoclast
Clinical Pearl Multiple myeloma causes a low anion gap.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
213
USMLE Step 2 l Internal Medicine
activating factor from the plasma cells and/or pathologic fractures at the time of diagnosis. Most commonly involved are the vertebrae, ribs, pelvic bones, and bones of the thigh and upper arm. If multiple myeloma is suspected with normal x-ray, consider MRI, CT, or PET. Serum B2
microglobulin is elevated in 75% of patients. Hypercalcemia from the destruction of bone is
common, as is an elevation in the BUN and creatinine from the damage to the kidney from the immunoglobulins, Bence-Jones protein, calcium, and hyperuricemia. A bone marrow biopsy with >10% plasma cells confirms a diagnosis of multiple myeloma. Bence-Jones protein is often not detected by a standard protein test on a urinalysis, which mainly is meant to detect albumin. A specific test for Bence-Jones protein involving acidification of the urine is required. Increased gamma globulin levels will increase the total protein and decrease the albumin level.
Treatment. Younger patients (age <70) should be treated with autologous bone marrow transplantation in an attempt to cure the disease. Older patients should receive a combination of melphalan and prednisone. Patients who are candidates for transplants should receive thalido- mide (or lenalidomide) and dexamethasone. Patients who are not candidates for transplants should receive melphalan, prednisone, and thalidomide. Hypercalcemia is treated initially with hydration and loop diuretics and then with bisphosphonates such as pamidronate.
Bortezomib is a proteasome inhibitor useful for relapsed myeloma or in combination with the other medications. It can be combined with steroids, melphalan, or lenalidomide (thalidomide).
Monoclonal Gammopathy of Uncertain Significance (MGUS)
Definition. The overproduction of a particular immunoglobulin by plasma cells without the systemic manifestations of myeloma such as bone lesions, renal failure, anemia, and hypercalcemia.
Etiology. The cause of MGUS is unknown. MGUS is a very common abnormality present in 1% of all patients age >50 and in 3% of those age >70. Some patients with MGUS may progress to multiple myeloma.
Clinical Presentation. Patients with MGUS have no symptoms. It is found on routine blood testing for other reasons.
Diagnosis. An elevated monoclonal immunoglobulin spike of serum protein electrophoresis (SPEP) in amounts lower than found in myeloma. The creatinine, calcium, and hemoglobin levels are normal. An elevated total serum protein is the clue to the diagnosis. There are no lytic bone lesions, and the bone marrow has <5% plasma cells. The beta-2 microglobulin level will be normal in most patients.
Treatment. Treatment is neither effective nor necessary.
LYMPHOMA
A 32-year-old woman comes to the office with a neck mass for the last several weeks. She also has fever, weight loss, and sweats.
Hodgkin Disease
Definition. A neoplastic transformation of lymphocytes particularly in the lymph node. It is characterized by the presence of Reed-Sternberg cells on histology which spreads in an orderly, centripetal fashion to contiguous areas of lymph nodes.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
214
Chapter 6 ● Hematology
Normal lymphocyte
Figure 6-6. Reed-Sternberg Cell
Reed-Sternberg Cell
Etiology. Although there is a clear increase in Hodgkin disease among relatives of those with the disease, there are no clear environmental or infectious etiologies for the disorder.
Hodgkin disease has bimodal age distribution—one peak in the 20s and 60s.
Clinical Presentation. Enlarged, painless, rubbery, nonerythematous, nontender lymph nodes are the hallmark of the disease. Patients may also develop what are labeled “B” symptoms, which are drenching night sweats, 10% weight loss, and fevers. Although pruritus is common in the disease, it is not one of the “B” symptoms. Cervical, supraclavicular, and axillary lymphadenopathy are the most common initial signs of disease. Lymphadenopathy may develop anywhere in the body, however. Extralymphatic sites such as splenic involvement, skin, gastric, lung, CNS, or any other organ may possibly be involved. Extralymphatic involve- ment is more common with non-Hodgkin lymphoma.
Staging is as follows:
Stage 1: 1 lymphatic group or single extra lymphatic site
Stage 2: 2 lymphatic groups or extra lymphatic sites on same side of the diaphragm
Stage 3: Involvement of lymphatic groups on both sides of the diaphragm or involve- ment of any extralymphatic organ contiguous to the primary nodal site
Stage 4: Widespread disease with involvement of diffuse extralymphatic sites such as bone marrow or liver
The staging is the same for both Hodgkin as well as non-Hodgkin lymphoma. In Hodgkin lymphoma, staging is the single most important predictor of outcomes.
Diagnosis. An excisional lymph node biopsy is the essential first step in determining the diagno- sis. After the initial diagnosis is determined by the biopsy, the most important step is to determine the extent of disease because the stage will determine the nature of the therapy, i.e., radiation versus chemotherapy. Chest x-ray or chest CT, abdominal CT, or MRI is used to determine if the disease is localized to the supraclavicular area. Lymphangiography and laparotomy are no longer routinely used for staging. CT scan is sensitive enough to detect any involved lymph nodes. A bone marrow biopsy is used to definitively determine if the disease is truly localized.
Note
Adverse Prognostic Factors
Large mediastinal lymphadenopathy
Age >40
“B” symptoms
↑ ESR
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
215
USMLE Step 2 l Internal Medicine
Size alone is insufficient to determine the content of some enlarged nodes. PET scan can also be used for that purpose.
Other labs tests that are often abnormal, but don’t directly alter the stage of the disease, include a CBC looking for anemia as well as increased white cell or platelet count. Eosinophilia is common. An elevated LDH level indicates an adverse prognosis. The ESR is useful prognosti- cally. Elevated liver function tests help determine the need for liver biopsy.
Treatment. Therapy is entirely based on the stage of the disease. Localized disease such as stage IA and IIA is managed predominantly with radiation. In the early stages (IA, IIA), adjunct chemotherapy may be used with radiation. All patients with evidence of “B” symptoms as well as stage III or stage IV disease are managed with chemotherapy. The most effective combination chemotherapeutic regimen for Hodgkin disease is ABVD (adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine). ABVD is superior to MOPP (mechlorethamine, Oncovin [vincris- tine], prednisone, and procarbazine) because ABVD has fewer adverse effects such as permanent sterility, secondary cancer formation, leukemia, aplastic anemia, and peripheral neuropathy.
Hodgkin disease has several histologic subtypes. Lymphocyte-predominant has the best prognosis, and lymphocyte-depleted has the worst prognosis. The histologic subtype does not alter anything described. The lab tests, staging, and treatments are the same.
216
Definition. The neoplastic transformation of both the B and T cell lineages of lymphatic cells. NHL causes the accumulation of neoplastic cells in both the lymph nodes as well as more often diffusely in extralymphatic organs and the bloodstream. The Reed-Sternberg cell is absent.
Etiology. There are a number of infectious and autoimmune disorders associated with the develop- ment of NHL. Their absence, however, by no means excludes the presence of NHL. Infections such as HIV, hepatitis C, Epstein-Barr, HTLV-I, and Helicobacter pylori predispose to the development of NHL. HIV and Epstein-Barr are both more often associated with Burkitt lymphoma. HIV can also be associated with immunoblastic lymphoma. The main point of knowing this is that they are both high-grade lymphomas with an aggressive progression of disease.
Clinical Presentation. Enlarged, painless, rubbery, nonerythematous, nontender lymph nodes are the hallmark of the disease. Patients may also develop what are labeled “B” symptoms, which are drenching night sweats, 10% weight loss, and fevers. Although pruritus is common in the disease, it is not one of the “B” symptoms. In this sense, NHL is the same as Hodgkin disease. The differ- ence is that Hodgkin disease is localized to cervical and supraclavicular nodes 80–90% of the time, whereas NHL is localized only 10–20% of the time. NHL is far more likely to involve extralym- phatic sites as well as to have blood involvement similar to chronic lymphocytic leukemia. CNS involvement is also more common with NHL. HIV-positive patients often have CNS involvement.
The staging system for NHL is the same as that for Hodgkin disease as described.
Diagnosis. The diagnosis of NHL rests initially on an excisional lymph node biopsy. After this, the most important step is to determine the stage of the disease to determine therapy. Although this is quite similar to that described for Hodgkin disease, there are several significant differ- ences because NHL is far more likely to be widespread at initial presentation. Lymphangiogra- phy is never necessary, and staging laparotomy is rarely needed. The bone marrow biopsy is more central as an initial staging tool. Because the presence of marrow involvement means the patient has Stage IV disease and therefore needs combination chemotherapy, further invasive testing such as the laparotomy is not necessary. As with Hodgkin disease anemia, leukopenia, eosinophilia, high LDH, and high ESR often accompany the disease. PET scanning is highly sensitive and specific for nodal and extranodal sites but not for bone marrow disease.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
Chapter 6 ● Hematology
Treatment. As with Hodgkin disease, local disease such as stage IA and stage IIA are treated predominantly with radiation, and all those with “B” symptoms as well as stages III and IV receive combination chemotherapy. Given the frequency of more widespread disease with NHL, however, this means few NHL patients are treated with radiation alone. The initial chemotherapeutic regimen for NHL is still CHOP (cyclophosphamide, hydroxy-adriamycin, oncovin [vincristine], prednisone). More elaborate chemotherapeutic regimens for NHL, of which there are many, are beyond the scope of what is necessary to know for the Step 2 exam.
CNS lymphoma is often treated with radiation, possibly in addition to CHOP. Relapses of NHL can be controlled with autologous bone marrow transplantation. Some patients with NHL express CD20 antigen in greater amounts. When this occurs, monoclonal antibody rituximab should be used. Rituximab is an anti-CD20 antibody that has limited toxicity and adds survival benefit to the use of CHOP. Thus, R-CHOP would then become first-line therapy. Prior to using R-CHOP, always test completely for hepatitis B and C, as rituximab can cause fulminant liver injury in those with active hepatitis B or C disease.
Tumor lysis syndrome
Tumor lysis syndrome (TLS) is an oncologic emergency caused by massive tumor cell lysis, with the release of large amounts of potassium, phosphate, and uric acid into the systemic circulation. Uric acid excretion can result in the precipitation of uric acid in the renal tubules; it can also induce renal vasoconstriction, reduced renal blood flow, and inflammation, resulting in acute kidney injury. Hyperphosphatemia with calcium phosphate deposition in the renal tubules can also cause acute kidney injury.
TLS most often occurs after the initiation of cytotoxic therapy in patients with high-grade lymphoma (particularly Burkitt’s and acute lymphoblastic leukemia), though it can occur spontaneously and with other tumor types having a high proliferative rate or large tumor burden.
Patients about to receive chemotherapy for a cancer with a high cell turnover rate—especially lymphomas and leukemias—should receive prophylactic oral or IV allopurinol plus adequate IV hydration to maintain high urine output (>2.5 L/day). Rasburicase may be used as an alternative to allopurinol and is reserved for those at high-risk for developing TLS. Alkaliza- tion of the urine as a treatment of TLS is controversial.
Clinical Recall
A 25-year-old man comes to the clinic complaining of enlarged, rubbery, non-erythematous, painless, non-tender cervical lymphadenopathy. He also admits to having weight loss, fever, and night sweats. What is the best initial diagnostic step in the management of this patient?
Complete blood count with erythrocyte sedimentation rate
PPD or IFN-gamma release assay with CXR
Upper endoscopy with gastrointestinal biopsy
Excisional lymph node biopsy
Abdominal CT
Answer: D
Note
Knowing each of the histologic subtypes of NHL is not necessary for the exam.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
217
USMLE Step 2 l Internal Medicine
Clinical Pearl
Platelet disorders can broadly be classified into 2 groups:
Quantitative (low platelet
count, eg, ITP)
Qualitative (normal platelet count but abnormal platelet function, eg, von Willebrand, Bernard Soulier)
PLATELET DISORDERS
Immune Thrombocytopenic Purpura (ITP)
Definition. Thrombocytopenia of unknown etiology.
Etiology. The idiopathic production of an antibody to the platelet, leading to removal of platelets from the peripheral circulation by phagocytosis by macrophages. The platelets are bound by the macrophage and brought to the spleen, leading to low platelet counts. ITP is often associated with lymphoma, CLL, HIV, and connective tissue diseases.
Clinical Presentation. Like all platelet disorders, the patient presents initially with signs of bleeding from superficial areas of the body such as the skin, nasal and oral mucosa, GI tract, urine, and vagina. The patient is generally young, more often female, and complains of epistaxis, bruising, hematuria, dysfunctional uterine bleeding, and sometimes GI bleeding. Petechiae, purpura, and ecchymoses are often found on exam. The patient is generally otherwise healthy. Splenomegaly should be absent.
Diagnosis. Thrombocytopenia is the major finding. A normal spleen on exam and on imaging studies such as an U/S is characteristic. Antiplatelet antibodies have a high sensitivity but poor specificity. The bone marrow should be filled with megakaryocytes indicating that there is a problem with platelet destruction and not platelet production. The bone marrow will also exclude other causes of thrombocytopenia such as primary or metastatic cancer, infiltration by infections such as tuberculosis or fungi, or decreased production problems such as drug, radiation, or chemotherapy effect on the bone marrow. The peripheral smear and creatinine should be normal, excluding other platelet destruction problems such as hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and disseminated intravascular coagulation.
Treatment. Prednisone is the initial therapy in almost all patients. Splenectomy is used in patients in whom very low platelet counts <10,000–20,000/mm3 continue to recur despite repeated courses of steroids. IVIG or RhoGAMTM may be used in patients with profoundly low platelet counts (<10,000 µL) or in patients at risk for life-threatening bleeding. Note that RhoGAM may only be used in Rh-positive patients. In those who recur after splenectomy, we use thrombopoietin agents romiplostim or eltrombopag. Rituximab has also been used.
A 22-year-old woman comes to the emergency department with epistaxis and heavy periods. She has a PT of 11 seconds (normal), a PTT of 40 seconds (prolonged), and 217,000/mm3 platelets.
Definition. An increased predisposition to platelet-type bleeding from decreased amounts of von Willebrand factor.
Etiology. An autosomal dominant disorder resulting in a decreased amount of von Willebrand factor. This is the most common congenital disorder of hemostasis. vWD results in a decreased ability of platelets to adhere to the endothelial lining of blood vessels. This is different from platelets aggregating with each other, which is mediated by fibrinogen. In vWD, aggregation is normal, whereas adherence is abnormal. It is not necessary to know the difference between the different subtypes of vWD for the Step 2 exam.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
218
Chapter 6 ● Hematology
Clinical Presentation. Patients with vWD manifest platelet-type bleeding such as that described for ITP. This is mucosal and skin bleeding such as epistaxis, petechiae, bruising, and menstrual abnormalities. Both platelet problems as well as clotting factor abnormalities can result in GI and urinary tract bleeding. There is often a marked increase in bleeding after the use of aspirin.
Diagnosis. The platelet count and appearance are normal. The bleeding time is increased particularly after the use of aspirin. The level of von Willebrand factor, also known as factor VIII antigen, is low. The ristocetin platelet aggregation test, which examines the ability of platelets to bind to an artificial endothelial surface (ristocetin), is abnormal. The PTT may be elevated in some patients because of a concomitant decrease in levels of factor VIII coagulant portion.
Treatment. Desmopressin acetate (DDAVP) is used for mild bleeding or when the patient must undergo minor surgical procedures. It releases subendothelial stores of von Willebrand factor. Factor VIII replacement is used if desmopressin is not effective and the bleeding continues.
Factor VIII replacement contains von Willebrand factor. This replaces the use of cryoprecipitate, which is now seldom necessary. Patients should not use aspirin. FFP is not useful.
(Factor 11 deficiency)
Symptoms
Petechiae
Purpura
Ecchymosis
Epistaxis
Gingival bleed
Menstrual bleeding
Symptoms
Hemarthrosis
Deep muscle bleeding
Organ bleeding
Causes
ITP (IgM auto Ab against GP2B3A rec)
TTP (auto Ab against Adams factor TS 13)
HUS (EHEC 0157:H7)
DIC
Reversible Causes
Uremia (inhibits platelet degranulation)
Drugs (NSAIDs, aspirin)
ADP rec blocker (clopidogrel, ticlopidine)
GP2B3A rec blocker (abciximab)
Irreversible Causes
Von Willebrand disease
Bernard Soulier disease (GP1B defect)
Glanzmann’s Thrombasthenia (GP2B3A rec defect)
PTT (prolonged)
PT/INR (normal)
Figure 6-7. Evaluation of Patients with Bleeding
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
219
USMLE Step 2 l Internal Medicine
COAGULOPATHY
Hemophilia A and B
Definition. The deficiency of factor VIII in hemophilia A and factor IX in hemophilia B resulting in an increased risk of bleeding.
Etiology. Both hemophilia A and B are X-linked recessive disorders resulting in disease in males. Females are carriers of the disease. Females do not express the disease because they would have to be homozygous, which is a condition resulting in intrauterine death of the fetus. Hemophilia A is far more common than B.
Clinical Presentation. Mild deficiencies (25% or greater activity) result in either the absence of symptoms or with symptoms only during surgical procedures or with trauma. More severe deficiency (<5–10% activity) can result in spontaneous bleeding. Factor-type bleeding is gener- ally deeper than that produced with platelet disorders. Examples of the type of bleeding found with factor deficiencies are hemarthrosis, hematoma, GI bleeding, or urinary bleeding. Bruising and central nervous system bleeding can also occur. Severe hemophilia is obvious in most patients by the age of 2. The disorder becomes apparent often at the time of circumcision.
Diagnosis. A prolonged PTT with a normal PT is expected. A factor deficiency is strongly suspected when a 50:50 mixture of the patient’s blood is created with a normal control and the PTT drops to normal. This is known as a “mixing study.” If the PTT does not correct with mixing, then an antibody inhibitor of the factor is suspected. The mixing study will only tell you that a deficiency is present; it will not tell you which specific factor is deficient. Specific factor VIII or IX levels are necessary to determine a precise diagnosis. This is true of both hemophilia A and B.
Treatment. Mild hemophilia can be treated with desmopressin (DDAVP). Desmopressin can also be used prior to surgical procedures in mild hemophiliacs. Desmopressin works by releasing subendothelial stores of factor VIII. More severe deficiencies are treated with replacement of the specific factor. Desmopressin does not work for hemophilia B.
Table 6-3. Causes of Prolonged PT or PTT
Inherited causes | vWF and factors VIII, IX, XI, or XII deficiencies | Prothrombin, fibrinogen, factor V, factor X, or combined factor deficiencies | |
Acquired causes |
Vitamin K deficiency
Liver disease
Warfarin use
Factor VII inhibitor
Heparin
Antiphospholipid antibody
Vitamin K deficiency
Liver disease
Disseminated intravascular coagulation
Supratherapeutic heparin or warfarin
Combined heparin and warfarin use
Direct thrombin inhibitors
Inhibitor of prothrombin, fibrinogen, or factor V or X
PT, prothrombin time; PTT, partial thromboplastin time; vWF, von Willebrand factor.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
220
Chapter 6 ● Hematology
Vitamin K Deficiency
Definition. The deficiency of vitamin K resulting in decreased production of factors II, VII, IX, and X.
Etiology. Vitamin K deficiency can be produced by dietary deficiency, malabsorption, and the use of antibiotics that kill the bacteria in the colon that produce vitamin K. The antibiotics most commonly associated are broad-spectrum drugs such as fluoroquinolones, cephalospo- rins, and other penicillin derivatives.
Clinical Presentation. Bleeding may mimic that of hemophilia and may occur at any site. Look for oozing at venipuncture sites.
Diagnosis. Both the PT and PTT are elevated. The PT usually elevates first and more severely. A correction of the PT and PTT in response to giving vitamin K is the most common method of confirming the diagnosis.
Treatment. Severe bleeding is treated with infusions of fresh frozen plasma. Vitamin K is given at the same time to correct the underlying production defect.
Liver Disease
Definition. Coagulopathy from the decreased production of clotting factors by the liver.
Etiology. Any severe liver disease or cirrhosis leads to a decreased production of the majority of clotting factors that are generally all made in the liver, except for factor VIII and von Willebrand factor. Factor VII is first factor to be depleted.
Clinical Presentation. Bleeding may occur at any site, but the GI tract is the most common site.
Diagnosis. Patients have an elevation of both the PT and PTT, but the PT elevates first and is often more severely affected. The disorder is clinically indistinguishable from vitamin K deficiency except that there is no improvement when vitamin K is given. A clear history of liver disease is often present, suggesting the diagnosis. Low platelet counts are often present from the hypersplenism that accompanies the liver disease.
Treatment. Fresh frozen plasma is used acutely to correct severe bleeding such as melena. Long-term management is based on the nature of the liver disease.
Disseminated Intravascular Coagulation (DIC)
Definition. Consumptive coagulopathy from major underlying illness resulting in consump- tion of both platelet and clotting factor type and occasionally thrombosis. The bleeding is associated with a marked production of fibrin degradation products such as d-dimers.
Etiology. Although essentially an idiopathic disorder, there is almost always a major underlying disease in the case history. Look for evidence of sepsis most commonly. Almost any disorder that results is cellular destruction and the release of tissue factor can initiate the cascade of consumption of platelets as well as clotting factors. These problems include rhabdomyolysis, adenocarcinomas, heatstroke, hemolysis from transfusion reactions, burns, head trauma, obstetrical disasters such as abruptio placenta and amniotic fluid embolism, as well as trauma, pancreatitis, and snakebites. Promyelocytic leukemia (M3) is a classic association.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
221
USMLE Step 2 l Internal Medicine
Gram-negative sepsis causes DIC by the releasing endotoxin. In acute promyelocytic leuke- mia (M3), the destruction of leukemic granulocyte precursors results in the release of large amounts of proteolytic enzymes from their storage granules, causing microvascular damage. Other malignancies may also cause DIC by augmenting the expression of various oncogenes that result in the release of tissue factor. DIC exists in acute and chronic forms.
Acute DIC develops when sudden exposure of blood to procoagulants (tissue factor, tissue thromboplastin) generates intravascular coagulation. The compensatory hemostatic mechanisms are quickly overwhelmed, and, as a consequence, a severe consumptive coagulopathy leading to hemorrhage develops.
In contrast, chronic DIC reflects a compensated state that develops when blood is continuously or intermittently exposed to small amounts of tissue factor. Compensa- tory mechanisms are not overwhelmed. Chronic DIC is more frequently observed in patients with solid tumors and in those with large aortic aneurysms.
Clinical Presentation. Bleeding from any site in the body is possible because of a decrease in both the platelet as well as clotting factor levels. Thrombosis is less common. Hemolysis is often present and may lead to acute renal failure, jaundice, and confusion.
Diagnosis. DIC is suspected when a patient has a serious underlying disorder as described with bleeding and there is elevation in both the PT and PTT with a decrease in the platelet count. The fibrinogen level is often low because it has been consumed. D-dimers and fibrin- split products are present in increased amounts, suggesting the consumption of all available elements of the coagulation system. The peripheral blood smear often shows the schistocytes as fragmented cells consistent with intravascular hemolysis.
Treatment. Because most patients present with severe bleeding, fresh frozen plasma (FFP) and sometimes platelet transfusions are necessary to correct the bleeding. Heparin is controversial and is rarely used except in those patients presenting predominantly with thrombosis. Don’t forget to correct the underlying disorder.
Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome
Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are two varieties of the same disease process with considerable overlap. There is no specific diag- nostic test, so the diagnosis is based on the clinical triad (HUS) or pentad (TTP).
Most cases of TTP are idiopathic and arise from inhibition of the enzyme ADAMTS13, which is responsible for cleaving large multimers of von Willebrand factor into smaller units. The increase in circulating multimers of vWF increase platelet adhesion to areas of endothelial injury, particularly the arteriole-capillary junctions.
Some cases of TTP are associated with specific diseases (cancer, HIV) and drugs (ticlopi- dine, clopidogrel, cyclosporine, and interferon) and are referred to as secondary TTP. ADAMTS13 activity is generally not as depressed in secondary TTP.
HUS predominantly affects children. Most cases are caused by a shiga-like toxin produced by E. coli O157:H7 although Campylobacter, Shigella, and some viruses have also been implicated. It is one of the most common causes of acute renal failure in childhood and carries up to 10% mortality.
HUS consists of a triad of hemolytic anemia, uremia, and thrombocytopenia. TTP has the same 3 findings, and is also associated with fever and neurologic problems. You do not have to have all 5 findings simultaneously to be considered to have TTP. The anemia in both will be intravas- cular in nature and will have an abnormal blood smear showing schistocytes, helmet cells, and fragmented red cells. LDH and reticulocyte count will be elevated and haptoglobin decreased.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
222
Chapter 6 ● Hematology
Treatment for TTP is plasmapheresis. Plasmapheresis is used to treat severe cases of HUS but is not established in the treatment of mild disease. Mild disease resolves spontaneously. Dipyri- damole may help treat TTP by preventing platelet aggregation.
Do not give antibiotics to those with possible HUS; if antibiotics are given, organism may release more toxins as it dies and may worsen the disease.
Do not transfuse platelets. Even if the platelet count is low, administering platelets can actually worsen the CNS and renal abnormalities by giving more platelets as a substrate to precipitate. Small platelet plugs are actually the cause of the problem.
Heparin-Induced Thrombocytopenia
Heparin-induced thrombocytopenia (HIT), a complication of heparin therapy, can occur with any form of heparin. It is more common with IV unfractionated heparin than with low molecular weight (LMW) heparin.
Type 1 HIT presents within first 2 days after exposure to heparin.
Non-immune-mediated disorder that results from the direct effect of heparin on platelet activation
This form of thrombocytopenia is benign, self-limited, and not associated with bleeding or increased risk of thrombosis
Type 2 HIT (generally referenced as HIT) occurs 4-10 days after exposure to heparin.
Has life- and limb-threatening thrombotic complications (low platelet count causes embolism, paradoxically)
Suspect HIT when a patient who is receiving heparin has a decreased platelet count, particularly if the drop is >50% of the baseline count, even if the platelet count nadir remains >150,000.
Clinically, HIT is not often marked by bleeding; the most common complication is venous thromboembolism (deep venous thrombosis, pulmonary embolism), and less often, arterial thrombosis (stroke, myocardial infarction). For that reason, the disorder is sometimes called heparin-induced thrombocytopenia and thrombosis (HITT). Thrombosis develops in approximately 20% of patients with HIT, with mortality as high as 30%.
Diagnosis of HIT is based on the combined clinical findings, thrombocytopenia characteris- tics, and lab studies of HIT antibodies (positive in ~85% of patients with type 2 HIT). Treat- ment begins with discontinuation of all heparin products (including heparin flushes of intravenous catheters), and later the administration of an alternative anticoagulant such as argatroban or lepirudin. Patients diagnosed with HIT should avoid all forms of heparin for life.
Warfarin
Warfarin (Coumadin) is the most widely prescribed anticoagulant for the prevention and treatment of thromboembolic disease. It was initially introduced as a pesticide against rodents, and long-acting forms of warfarin are still used for this purpose.
Warfarin anticoagulates by inhibiting an enzyme that recycles oxidized vitamin K to its reduced form. Warfarin does not antagonize the action of vitamin K, but rather antagonizes vitamin K recycling. Once vitamin K is reduced, the vitamin K dependent factors (factors 2,7,9,10) are eventually reduced (3-5 days).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
223
USMLE Step 2 l Internal Medicine
Despite its efficacy, treatment with warfarin has several limitations.
Many commonly used medications interact with warfarin, as do some foods— particularly green vegetables—since they typically contain large amounts of vitamin K.
Warfarin activity has to be monitored by the PT and international normalized ratio (INR) to ensure an adequate yet safe dose (typically INR 2−3 is considered adequate and safe anticoagulation). The pharmacologic action of warfarin may always be reversed by fresh vitamin K.
Table 6-4. Recommended Management of a Supratherapeutic INR
INR | Bleeding Present | Recommended Action |
No | ||
Lower warfarin dose, or
Omit a dose and resume warfarin at a lower dose when INR is in therapeutic range, or
No dose reduction needed if INR is minimally prolonged
Omit the next 1–2 doses of warfarin, monitor INR more frequently, and resume treatment at a lower dose when INR is in therapeutic range, or
Omit a dose and administer 1–2.5 mg oral vitamin K*
INR: International Normalized Ratio; Ther: therapeutic INR range for the patient in question.
*Preferred in patients at increased risk for bleeding (e.g., history of bleeding, stroke, anemia).
Clinical Recall
What is the most appropriate step in the management of a patient with heparin-induced thrombocytopenia and thrombosis?
Continue heparin and administer warfarin
Discontinue heparin and administer argatroban
Discontinue the heparin substitute with warfarin
Continue heparin and add lepirudin
Continue heparin and monitor closely
Answer: B
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
224
InfectioCuhsapDtiesreaTsiteles #7
Learning Objectives
Provide an overview of common antibiotics and their uses
Describe the unique conditions and considerations for infections which occur in the CNS, head, neck, lung, pericardium, endocardium, GI tract, urinary tract, bones, and joints
Present the treatment of acute herpes viral hepatic infections
Describe the presentation and management of Lyme disease and Rocky Mountain spotted fever
Describe the epidemiology, presentation, and treatment of genital and sexually transmitted diseases
Describe the epidemiology, presentation and management of AIDS and related opportunistic infections
ANTIBIOTICS
Antibiotics can be grouped by their chemical class or by the type of organism they are effective against. The organisms that cause specific diseases do not change much over time. For example, MRSA, Staphylococcus aureus is still the most common cause of osteomyelitis, and Escherichia coli is still the most common cause of pyelonephritis.
What does change over time is the antibiotic that is effective against each organism and the sensitivity pattern of each organism.
Gram-Positive Cocci
Semisynthetic penicillinase-resistant penicillins
Staphylococcal and streptococcal organisms are effectively treated by medications such as the semisynthetic penicillins, including oxacillin, cloxacillin, dicloxacillin, and nafcillin. These agents are exclusively effective against Gram-positive cocci, in particular staphylococci.
Note
Do not use vancomycin if the organism is oxacillin-sensitive.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
225
USMLE Step 2 l Internal Medicine
Note
On the exam, your answers should correspond most specifically to the organism you are treating. If you are treating a sensitive Staph aureus or Strep, answer with a specific Gram-positive drug.
Do not give an answer which provides more coverage than needed, unless there is evidence to support the presence of other organisms. If you are treating a Gram- positive infection, answer with a first-generation agent.
Methicillin belongs to this group of antibiotics as well, and was one of the original drugs developed in this class. It is not used clinically, however, because it may cause interstitial nephritis. Thus, the term “methicillin-sensitive” or “methicillin-resistant Staphylococcus aureus (MRSA)” is somewhat of a misnomer because methicillin is not actually used. When this term is used, think of the drugs oxacillin, cloxacillin, dicloxacillin, and nafcillin.
When Staphylococcus is sensitive to the semisynthetic penicillins, and concurrent Gram-nega- tive infection is not suspected, these are the ideal agents. They are more effective than vanco- mycin when the organism is sensitive. These drugs are also sometimes referred to as “beta- lactamase-resistant penicillins” or “antistaphylococcal penicillins.” Nevertheless, the latter term is somewhat misleading because they are also effective against a number of streptococci, such as S. pneumoniae, the Viridans group, and groups A, B, C, and G Strep.
Penicillin G, penicillin VK, ampicillin, and amoxicillin
These agents are effective against streptococci, such as S. pyogenes, viridans group streptococ- ci, and S. pneumonia, but not against staphylococci.
All of the agents can be useful against Gram-negative bacteria such as Neisseria.
Ampicillin and amoxicillin are effective against staph only when ampicillin is combined with the beta-lactamase inhibitor sulbactam or when amoxicillin is combined with clavulanate.
Both ampicillin and amoxicillin are effective against enterococci and Listeria.
The first- and second-generation cephalosporins all cover the same range of organisms that the semisynthetic penicillins cover, i.e., staphylococci and streptococci, plus some Gram- negative organisms.
First-generation agents (cefazolin, cefadroxil, cephalexin) only reliably cover Morax- ella and E. coli.
Second-generation agents (cefoxitin, cefotetan, cefuroxime, cefprozil, loracarbef) will cover everything a first-generation cephalosporin covers, as well as a few more Gram-negative bacilli such as Providencia, Haemophilus, Klebsiella, Citrobacter, Morganella, and Proteus.
Third-generation agents, particularly ceftazidime, are not reliable in their staphylo- coccal coverage.
Fourth-generation cephalosporins such as cefepime will cover staph and strep, although this should never be the answer when the infection is exclusively Gram-positive.
For those with allergy to penicillin, there is only a <1% risk of cross-reaction with cephalo- sporins. When this reaction occurs it is seldom an anaphylactic reaction.
When the allergic reaction is described as a rash, a cephalosporin can safely be used.
When the allergic reaction is severe, e.g. anaphylaxis, a cephalosporin should not be used.
For minor infections, use a macrolide (clarithromycin or azithromycin), or one of the new fluoroquinolones (levofloxacin, gemifloxacin, or moxifloxacin).
For serious infections in those with a life-threatening penicillin allergy, use vancomy- cin, linezolid, or daptomycin.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
226
Chapter 7 ● Infectious Diseases
Macrolides, fluoroquinolones, and clindamycin
For Gram-positive infections, macrolides (erythromycin, clarithromycin, azithromycin), fluoroquinolones (levofloxacin, gemifloxacin, moxifloxacin), and clindamycin are alternatives to penicillins and cephalosporins. Macrolides should not be used for serious staph infection.
The new quinolones are very good for streptococcal infections, particularly Strep pneumoniae in the absence of outright penicillin-resistance. They are also sufficient against staph. Cipro- floxacin is a quinolone as well, but it does not cover Strep pneumoniae.
Vancomycin, linezolid, tigecycline, ceftaroline, telavancin
For Gram-positive infections, vancomycin, linezolid, and tigecycline are effective. Alterna- tives include ceftaroline, telavancin, daptomycin, and quinupristin/dalfopristin.
When there is a life-threatening penicillin-allergy or MRSA, use the agents listed above. MRSA is primarily treated with vancomycin.
Quinupristin/dalfopristin are also effective against vancomycin-resistant enterococci. Ceftaro- line is used like a third-generation cephalosporin, such as ceftriaxone, combined with a MRSA agent, such as vancomycin. Ceftaroline is the only cephalosporin to cover MRSA. These medications should not be used if the organism is sensitive to methicillin.
Penicillins
Penicillins (piperacillin, ticarcillin, mezlocillin) are fully active against the full range of Gram- negative bacilli, such as Pseudomonas, as well as the Enterobacteriaceae. Enterobacteriaceae include E. coli, Proteus, Enterobacter, Citrobacter, Morganella, Serratia, and Klebsiella. They are only active against staph when combined with a beta-lactamase inhibitor such as piperacil- lin/tazobactam or ticarcillin/clavulanate. Ampicillin/sulbactam and amoxicillin/clavulanate will also cover staph and Gram-negative bacilli, but not Pseudomonas.
All penicillins will cover sensitive streptococci, but if the patient has only a sensitive strep, give a narrower agent, such as penicillin G or penicillin VK.
Cephalosporins
Third- and fourth-generation agents (ceftazidime; cefotaxime; ceftriaxone; cefotaxime, and cefepime) are fully active against the full range of Gram-negative bacilli, such as the Entero- bacteriaceae. Only ceftazidime and cefepime will cover Pseudomonas. Cefepime also covers staph.
Second-generation agents cover some of the Enterobacteriaceae, but not Pseudomonas. Although predominantly for use against Gram-negative organisms, ceftriaxone and cefotaxime are the best answers for penicillin-insensitive pneumococci-causing meningitis or pneumonia.
Quinolones
Quinolones (ciprofloxacin, levofloxacin, gemifloxacin, moxifloxacin, ofloxacin) cover most of the Enterobacteriaceae, such as E. coli, Proteus, Enterobacter, Haemophilius, Moraxella, Citrobacter, Morganella, Serratia, and Klebsiella. Only ciprofloxacin will reliably cover Pseudomonas.
Note
Daptomycin, ceftaroline, and tigecycline are drugs also effective against MRSA.
Note
Cephalosporins are safe in penicillin allergy if it is only a rash.
Clinical Pearl Ceftriaxone does not have adequate pseudomonal
coverage.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
227
USMLE Step 2 l Internal Medicine
Note
Sensitive Staph should not be treated with TMP/SMZ, doxycycline, or clindamycin.
The new fluoroquinolones (moxifloxacin, levofloxacin, and gemifloxacin) are also active against Gram-positive cocci, in particular Strep pneumoniae. They are among the first-line therapies for empiric treatment of pneumonia because they will also cover Mycoplasma, Chlamydia, and Legionella.
Aminoglycosides and monobactams
Aminoglycosides (gentamicin, tobramycin, amikacin) and monobactams (aztreonam) have essentially the same Gram-negative coverage as listed above for the other agents. Although aminoglycosides can be synergistic with a penicillin in the treatment of staph, they are essentially exclusively Gram-negative agents. Aztreonam is exclusively a Gram-negative agent, with no strep or staph coverage at all.
Carbapenems
Carbapenems (imipenem, meropenem, ertapenem, doripenem) are fully active against Enterobacte- riaceae and Pseudomonas; they are similar in Gram-negative coverage to the aminoglycosides and third-generation cephalosporins. In addition, they have excellent staph and anaerobic coverage.
Although effective in polymicrobial infections, they are best used in Gram-negative infections.
All carbapenems are equally effective against anaerobes, as compared to metronidazole. Ertapenem will not cover Pseudomonas.
The agent most active against anaerobes is metronidazole. Metronidazole has some advantages against anaerobic Gram-negative bacteria in the bowel, such as Bacteroides fragilis. Metronidazole is the first-line agent against Clostridium difficile. Clindamycin is less active against intra-abdominal anaerobes, but may have some advantages against the anaerobic streptococci found in the mouth.
The other agents with excellent anaerobic coverage virtually equal to metronidazole are the carbapenems and the beta-lactam/beta-lactamase combination medications such as piperacillin/tazobactam, ticarcillin/clavulanate, ampicillin/sulbactam, or amoxicillin/
clavulanate. The second-generation cephalosporins cefoxitin and cefotetan have fair activity against anaerobes, but they are less effective.
Skin MRSA
TMP/SMZ, clindamycin, doxycycline, and linezolid are oral agents useful for MRSA. Use these oral agents for minor MRSA infections. TMP/SMZ, clindamycin, and doxycycline cannot be used for MRSA bacteremia.
CENTRAL NERVOUS SYSTEM INFECTIONS
Meningitis
A 45-year-old man is brought to the emergency department with 1–2 days of fever, headache, nausea, and vomiting. On physical examination he is found to have neck stiffness and photophobia.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
228
Chapter 7 ● Infectious Diseases
Meningitis is an infection or inflammation of the meninges, which is the connective tissue covering the central nervous system (CNS). Most cases arise sporadically, and the precise method of spread of the microorganism into the CNS stem is not determined.
Overall, most meningitis cases are caused by viruses.
Streptococcus pneumoniae is the most common cause of bacterial meningitis for all patients beyond the neonatal period.
Neisseria meningitidis, spread by respiratory droplets, is the most common cause of meningitis in adolescents.
Listeria monocytogenes is more common in those with immune system defects, particularly of the cellular (T-cell) immune system and sometimes neutrophil defects. These defects include HIV, steroid use, leukemia, lymphoma, and various chemothera- peutic agents. Since neonates and the elderly have decreased T-cell immune func-
tion, Listeria is more common in them.
Even with immune deficits, Streptococcus pneumoniae is still the most common etiology—it is just that Listeria is more common in these patients, as compared to fully immunocompetent patients. Staphylococcus aureus is more common in those who have had any form of neurosur- gery because instrumentation and damage to the skin introduce the organism into the CNS. Cryptococcus is more common in those who are HIV positive and who have profound decreas- es in T-cell counts to levels <100 cells.
Rocky mountain spotted fever (RMSF) is common in those who have been exposed to ticks in the appropriate geographic area. The areas with the highest RMSF infection are in the mid-Atlan- tic areas, such as the Carolinas, Kentucky, and Tennessee. Lyme disease can also cause meningitis and is more common in the Northeast, such as Massachusetts, Connecticut, New York, and New Jersey. Tuberculosis and syphilis are also associated with meningitis. Viruses are the most common cause of aseptic meningitis, a syndrome in which patients present in a manner similar to bacterial meningitis, but CSF analysis mostly reveals a lymphocytic pleocytosis and bacterial cultures are negative. Viruses causing aseptic meningitis include entero viruses, arboviruses (St. Louis encephalitis virus, West Nile virus), HIV, herpes simplex, and lymphocytic choriomeningi- tis virus. In the past, most of these were not diagnosed, but with the availability of PCR-based testing, more cases of aseptic meningitis are being accurately classified. Group B Streptococcus (Streptococcus agalactiae) is the most common cause of meningitis in the neonatal period.
The spread of the organism into the CNS can be by sporadic (unknown) mechanisms or by means of contiguous local infection or by hematogenous spread. Local infections that can lead to meningitis include otitis media, sinusitis, mastoiditis, and dental infections. Hematogenous spread could possibly occur from any infection but is more common with endocarditis and pneumonia.
Clinical Presentation. Regardless of microbiologic etiology, all forms of meningitis present with fever, photophobia, headache, nuchal rigidity (neck stiffness, positive Kernig and Brudzinski signs), as well as nausea and vomiting. Altered mental status is possible, and can make a patient appear to have encephalitis. Any form of CNS infection can present with seizures. Focal neurologic deficits can also occur, the most common being visual field and cranial nerve deficits. The most common long-term neurologic deficit from bacterial meningitis is damage to the 8th cranial nerve.
Rash is associated with several types of meningitis.
Petechial rash is suggestive of Neisseria
Rash on the wrists and ankles with centripetal spread toward the body is suggestive of RMSF
Note
In the past, Haemophilus influenzae was the most common cause of meningitis in children, but this has markedly decreased with
the Haemophilus type B vaccine.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
229
USMLE Step 2 l Internal Medicine
Clinical Pearl
In patients presenting with symptoms and signs of meningitis, treat empirically for bacterial meningitis while awaiting test results from the lumbar puncture.
Facial nerve palsy is suggestive of Lyme disease; the target-like erythema migrans rash of Lyme disease is seldom present by the time the meningitis develops
Pulmonary symptoms or abnormal chest x-ray suggest tuberculosis
Diagnosis. Lumbar puncture is essential for establishing the diagnosis. CT scan of the head is the best initial diagnostic test if the patient has papilledema, focal motor deficits, new onset seizures, severe abnormalities in mental status, or immunocompromised status (HIV, immu- nosuppressive medications, post-transplantation). If none of the above is present, a lumbar puncture can be safely done without doing a CT scan of the head first, which can significantly delay the diagnosis. If lumbar puncture is delayed >20–30 minutes for any reason, the best initial step is to give an empiric dose of antibiotics.
The most accurate test for bacterial meningitis on the lumbar puncture is the culture of the CSF. The results are always delayed for several days, however, and are rarely available at the time the initial therapy must be instituted. Protein levels are elevated most commonly with bacterial meningitis, but they can be elevated in any type of meningitis. Elevated protein level and/or decreased glucose level by themselves are relatively nonspecific findings. The opening pressure can be elevated with any cause of meningitis.
The Gram stain has a limited sensitivity and is positive in 50–70% of patients at most. When positive, however, the Gram stain has a high degree of specificity.
Initially, the most useful test is the cell count. Although elevated cell count by itself is nonspecific, the differential of the cells is useful. Only bacterial meningitis gives thousands of cells that are all neutrophils. A mild-to-moderate elevation in lymphocytes, with several dozen to several hundred cells, can occur with viral infection, Rickettsia, Lyme disease, tuberculosis, syphilis, or fungal (cryptococcal) etiology. Normal CSF cell count is <5 cells/mm3, which should be predominantly lymphocytes.
Specific diagnosis of nonbacterial meningitis is based on the nature of the organism. Lyme disease and RMSF are best detected with a specific immunologic response and serology. Crypto- coccus neoformans is detected initially with an India ink test and then later with an elevation in the serum and CSF cryptococcal antigen titer. Syphilis is confirmed by the presence of a positive VDRL or FTA on CSF. TB is rarely detected by AFB smear. Culture for TB has a much higher yield, particularly on several repeated LPs. PCR can also aid in the diagnosis of TB.
Treatment. Empiric therapy of bacterial meningitis in adults is best achieved with vancomycin (because of the increasing prevalence worldwide of pneumococci with decreasing sensitivity to penicillins) plus a third-generation cephalosporin such as ceftriaxone. Ampicillin is added to those with immune defects to cover Listeria and for patients age >50 or ≤1 month. You will have to recognize the risks, such as HIV, steroid use, pregnancy, or hematologic malignancies in the case description. Listeria is resistant to all forms of cephalosporins. Vancomycin is used if you know you have definite or suspected pneumococcal resistance to penicillin or if there is a chance of staphylococcal infection after neurosurgery. Lyme disease is best treated with ceftriaxone. Cryptococcus is treated initially with amphotericin. This is followed by fluconazole therapy in HIV-positive patients for life or until the patient is on HAART (highly active antiretroviral therapy) and is asymptomatic with CD4 count >100/μL for at least 3–6 months. Neurosyphilis is treated with high-dose IV penicillin. TB meningitis is treated in the same fashion as you would use for pulmonary TB (though a longer duration of 9–12 months of therapy is given). Steroid use in adult meningitis is appropriate for TB meningitis and bacterial meningitis. There is no treatment currently proven useful for viral (or aseptic) meningitis.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
230
Chapter 7 ● Infectious Diseases
Dexamethasone (corticosteroid) therapy for patients with bacterial meningitis decreases mortality and rates of deafness. The rationale for this is the inflammatory response elicited in the subarachnoid space due to bacterial cell wall lysis after antibiotics are administered; this inflammatory reaction can worsen morbidity and mortality due to bacterial meningitis.
Accordingly, dexamethasone given 15–20 minutes before or concurrently with antibiotics should produce improved outcomes (morbidity and mortality); the benefit is greatest for patients with pneumococcal meningitis. Dexamethasone should be continued for 4 days if bacterial meningitis is confirmed (positive Gram stain of CSF fluid or >1000 WBCs within the CSF can be taken as confirmation of bacterial meningitis) and discontinued if the etiology is nonbacterial (viral, fungal, etc.).
Clinical Recall
Encephalitis
A young man is brought to the emergency department by his friends because of 1–2 days of confusion and strange behavior. He had been originally complaining of a headache and fever. On the day of admission he became markedly worse and is now delirious. He is generally healthy. On physical examination you find a lethargic, confused man with an elevated temperature. You are unable to determine if he has focal neurologic findings or to obtain an accurate neurologic exam because his confusion makes him unable to follow commands.
Encephalitis is an infection of the brain, whether in the meninges or the brain parenchyma. Al- though any bacterial, protozoal, or rickettsial infection can cause encephalitis, most cases are caused by viruses, with herpes simplex (usually type I [HSV-1]) the most common.
Varicella-zoster virus, CMV, enteroviruses, Eastern and Western equine encephalitis, St. Louis encephalitis, and West Nile encephalitis are significantly less common causes.
Patients present with fever and headache but these findings are nonspecific. Altered mental status with fever and headache is the primary clue to the diagnosis. Any level of neurologic deficit may occur, ranging from slight confusion to lethargy or coma. Focal deficits of any kind can occur. Neck stiffness similar to that found in meningitis can occur, making it difficult to distinguish encephalitis from meningitis. Seizures may also occur.
Clinical Pearl Encephalitis usually presents with altered mental status,
erratic behavior, etc (brain
parenchyma involved).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
231
USMLE Step 2 l Internal Medicine
Diagnosis. Although CT or MRI of the head should be performed, it cannot give a specific diagnosis. HSV has a predilection for involvement of the temporal lobes, which can sometimes be seen on CT. Lumbar puncture is the key to the diagnosis. Formerly, a brain biopsy was necessary, but PCR (polymerase chain reaction) amplification techniques have virtually eliminated that need. PCR for HSV has a 98% sensitivity and >95% specificity, making it at least equal to the biopsy.
Treatment. HSV encephalitis is best treated with IV acyclovir. Although famciclovir and valacyclovir have activity against HSV, they are not available intravenously. Ganciclovir or foscarnet are active against CMV. Acyclovir-resistant herpes is treated with foscarnet.
Brain Abscess
Brain abscess is a collection of infected material within the brain parenchyma. Bacteria can spread into the brain from contiguous infections such as otitis media, sinusitis, mastoiditis, or dental infection. Organisms may also spread through the bloodstream from endocarditis or pneumonia and seed the brain. Toxoplasmosis can reactivate in those with severe HIV disease when CD4 counts are very low (<50–100/μL). Brain abscesses most commonly have Strepto- coccus in 60–70%, Bacteroides in 20–40%, Enterobacteriaceae in 25–35% and Staphylococcus in 10%, and are often polymicrobial. Because of the diversity of the organisms potentially involved, it is difficult to have a single standard therapy.
Headache is the most common symptom. Fever can be present. Focal neurologic deficits are the initial complaint in about 60% of patients. Seizures may occur, as with any form of anatom- ic abnormality of the CNS. All CNS infections can cause seizures.
aic.cuhk.edu.hk/web8
Figure 7-1. CT Scan Demonstrating Large Cerebral Abscess
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
232
Chapter 7 ● Infectious Diseases
Diagnosis. The initial test is the CT scan. Contrast is used to help identify the lesion, although CNS malignancy enhances with contrast as well. MRI is more accurate than the CT scan, although no radiologic test alone can give the precise etiology. In the case of bacterial brain abscess, examination of the abscess fluid (obtained by stereotactic aspiration or surgical excision of the abscess) for Gram stain and culture is essential. In HIV-positive patients, 90% of brain lesions will be either toxoplasmosis or lymphoma. This is the only circumstance where empiric therapy is sufficient to establish a specific diagnosis. If the lesion responds to 10–14 days of therapy with pyrimethamine and sulfadiazine, continue to administer this therapy, as it accurately predicts cerebral toxoplasmosis.
Treatment. Almost always, successful treatment requires a combination of surgical and medical management. Stereotactic aspiration (preferred) and surgical excision of the abscess are the methods used; the latter is rarely used nowadays because of significant complications.
With the exception of HIV-positive patients who are best treated with pyrimethamine and sulfadiazine, therapy should be based on the specific etiology found. One example of a combination of therapy is penicillin, metronidazole, and a third-generation cephalosporin, such as ceftazidime. Penicillin would cover the streptococci, metronidazole the anaerobes, and ceftazidime the Gram-negative bacilli.
Otitis Media
Otitis media is an infection of the middle ear between the eustachian tube and the tympanic membrane. Viral upper respiratory infection can cause edema of the eustachian tube, which often leads to middle ear infection. The most common organisms are Strep pneumoniae (35–40%), H. influenzae (nontypeable; 25–30%), and Moraxella catarrhalis (15–20%). Viruses probably account for the rest of the cases. This is roughly the same breakdown of organism type and frequency that occurs in bronchitis and sinusitis.
Patients complain of ear pain, fever, and decreased hearing. On physical examination a red, bulging tympanic membrane is found, with loss of the light reflex. The most sensitive clinical finding is immobility of the membrane on insufflation of the ear with air. Perforation of the tympanic membrane with otorrhea occurs rarely.
Diagnosis is made through physical examination of the ear. Radiologic tests are not useful. A specific bacteriologic diagnosis can be obtained with tympanocentesis for culture, but that is rarely performed.
Treatment. Oral therapy with amoxicillin is still the best initial therapy. Amoxicillin-clavulanate is used if there has been recent amoxicillin use or if the patient does not respond to amoxicillin. Other alternatives to amoxicillin-clavulanate are second-generation cephalosporins, such as cefuroxime, loracarbef, or cefprozil, or third-generation agents, such as cefdinir or cefixime.
Patients with severe penicillin allergy should receive a macrolide such as azithromycin or clarithromycin. New fluoroquinolones such as levofloxacin, moxifloxacin, or gatifloxacin are microbiologically acceptable but are broader coverage than necessary and should not be used in children (concern for arthropathy). TMP/SMZ is sometimes used but is poorly active against Streptococcus pneumoniae.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
233
USMLE Step 2 l Internal Medicine
Sinusitis
A young woman comes to the office with several days of facial pain, a headache, cough, fever, and discolored nasal drainage. On physical examination tenderness over the maxillary sinuses and decreased transillumination of the maxillary sinuses is found.
Sinusitis is an infection of the sinuses. The most common site is the maxillary sinus, followed by ethmoid, frontal, and sphenoid sinuses.
Figure 7-2. Sinusitis
Viruses are responsible for most cases of sinusitis. Bacterial organisms that cause sinusitis are the same ones causing otitis media.
Patients complain of facial pain, headache, postnasal drainage, and purulent nasal drainage. Headache is common and is worse when the patient leans forward. Fever occurs in about 50% of cases. Tooth pain also occurs because of the proximity of the sinuses to the teeth.
Diagnosis. Obvious cases of sinusitis do not always need radiologic confirmation prior to treatment. Sinus x-rays are of little value, and routine imaging as a rule is not recommended. If imaging is required because of concern for complications, uncertain diagnosis, or lack of response to treatment, CT scan of the sinuses is the test of choice since it provides greater detail. Occasionally, sinus puncture is necessary to confirm a specific bacteriologic etiology, particularly when the patient does not respond to therapy or if there are frequent recurrences.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
234
Chapter 7 ● Infectious Diseases
Treatment. Mild or acute uncomplicated sinusitis can be managed with decongestants, such as oral pseudoephedrine or oxymetazoline sprays. More severe pain with discolored nasal discharge is treated with antibiotics. The drugs used are in the same order and type as those listed above for otitis media because the microbiology is almost identical.
Most cases of viral rhinosinusitis resolve in 7–10 days with symptomatic management (antihis- tamines, NSAIDS, and decongestants). If symptoms persist beyond that point or get worse, antibiotics should be considered.
Pharyngitis
Pharyngitis is irritation or inflammation of the back of the throat (or the pharynx). Although most pharyngeal infections are caused by viruses, the most important cause is group A
beta-hemolytic streptococci (S. pyogenes). This is because of the possibility of the organism progressing on to rheumatic fever or glomerulonephritis. S. pyogenes only accounts for 15–20% of cases of pharyngitis.
Sore throat with cervical adenopathy and inflammation of the pharynx with an exudative covering is highly suggestive of S. pyogenes. Most viruses do not give an exudate, although the Epstein-Barr virus can. Mild S. pyogenes infections may not give an exudate, and this is one of the reasons diagnostic testing is useful. Hoarseness and cough are not suggestive of pharyngitis.
Wikipedia, James Heilman, MD
Figure 7-3. Strep Throat
Diagnosis. The rapid streptococcal antigen test is 80% sensitive but >95% specific. A positive test can be considered the equivalent of a positive culture, whereas a negative test should be confirmed with a culture.
Treatment. Penicillin remains the mainstay of therapy. Macrolides and oral, second- generation cephalosporins are alternatives in the penicillin-allergic patient.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
235
USMLE Step 2 l Internal Medicine
Note
Flu vaccine is indicated annually for everyone age >6 months.
Influenza
Influenza is a systemic viral illness from influenza A or B, usually occurring in an epidemic pattern and transmitted by droplet nuclei. Influenza can lead to damage to the respiratory epithelium, leading to sinusitis, otitis media, bronchitis, and pneumonia.
Patients present with a systemic illness characterized by fever, myalgias, headache, and fatigue. Upper respiratory symptoms tend to predominate. These include runny nose (coryza), nonproductive cough, sore throat, and conjunctival injection.
Diagnosis is initially confirmed with rapid antigen detection methods of swabs or washings of nasopharyngeal secretions. Viral culture is the most accurate test but is usually not available rapidly enough to make it useful in acute patient management.
Treatment. Symptomatic therapy with acetaminophen and antitussives is useful. Specific antiviral medications for both influenza A and B are the neuraminidase inhibitors oseltamivir and zanamivir. They should be used within 48 hours of the onset of symptoms to limit the duration of symptoms. Amantadine and rimantadine should not be used in the empiric therapy of influenza. Influenza vaccine is recommended annually in the general public.
The most important candidates for vaccination are those with chronic lung and cardiac disease, pregnant women in any trimester, residents of chronic care facilities, health-care work- ers, immunosuppressed patients, and those with diabetes and renal dysfunction. Influenza vaccine is contraindicated in those who are highly allergic to eggs and which would result in anaphylaxis.
10–14 days of therapy with pyrimethamine and sulfadiazine
HSV PCR followed by IV acyclovir
LP with culture of CSF fluid
Answer: C
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
236
Chapter 7 ● Infectious Diseases
LUNG INFECTIONS
Bronchitis
A 63-year-old man comes to the office with a cough productive of yellowish sputum for the last several days. He has smoked 1 pack of cigarettes a day for the last 30 years. On physical examination the lungs are clear and temperature is 38.3 C (101 F). Chest x-ray is normal.
Bronchitis is an infection of the lung, limited to the bronchial tree with limited involvement of the lung parenchyma. Acute exacerbations of chronic bronchitis (COPD) are often difficult to distinguish from a pneumonia until chest x-ray is performed.
Acute bronchitis is an acute inflammation of the tracheobronchial tube. The vast majority of cases are caused by viruses. S. pneumoniae and H. influenzae have not been implicated. A small percentage of nonviral cases are due to M. pneumoniae, C. pneumoniae, and B. pertussis.
The most common organisms responsible for chronic bronchitis are similar to those causing sinusitis and otitis media (Streptococcus pneumoniae, nontypeable Haemophilus influenzae, and Moraxella). Viruses account for a significant percentage but are often not confirmed. Cigarette smoking is the most common causative factor; even 1 cigarette per day is enough to paralyze the cilia, which clear the bronchial tree of mucus and inhaled impurities, for 24 hours.
Patients present with a cough often accompanied by sputum production. A bacterial etiology is suggested by discolored sputum, but it is impossible to determine the specific bacterial etiology by sputum characteristics alone. Although the lung exam may reveal rales, patients most commonly have clear lungs. Signs of consolidation, such as increased fremitus, are absent.
Low-grade fever may be present, but patients are most commonly afebrile.
Diagnosis. Signs of respiratory infection, such as cough and sputum, with a normal chest x-ray confirm the diagnosis.
Treatment. Mild acute cases often do not require therapy because they are often caused by viruses that resolve spontaneously. Acute exacerbations of chronic bronchitis can be treated with amoxicil- lin, doxycycline, or TMP/SMZ, if there has not been recent antibiotic use. Repeated infection or patients not responding to amoxicillin should be treated with any of the following: amoxicillin/ clavulanate, clarithromycin, azithromycin, oral second- or third-generation cephalosporins, or the new fluoroquinolones, gemifloxacin, levofloxacin, or moxifloxacin.
Lung Abscess
A 58-year-old alcoholic man was admitted last night for several weeks of cough, sputum, and fever. He has lost 15 pounds and is feeling weak. On initial examination he is febrile and appears thin. He has very poor dentition. The lung examination is normal. The patient also exhibits a foul odor on the oral examination.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
237
USMLE Step 2 l Internal Medicine
Note
Pneumonia is the only cause of death from an infectious disease in the top 10 causes of death in the United States.
Lung abscess is necrosis of the pulmonary parenchyma caused by microbial infection.
90% have at least some anaerobes involved
The most commonly implicated anaerobes are Peptostreptococcus, Prevotella, and
Fusobacterium species, which are oral anaerobes found in the gingival crevices
45% only anaerobic, 45% mixed with aerobes, 10% aerobes only
Aerobic bacteria, most frequently involved are S. aureus, E. coli, Klebsiella, and
Pseudomonas
85–90% of cases have a clear association with periodontal disease or some predisposition to aspiration (e.g., altered sensorium, seizures, dysphagia). Pulmonary infarction, cancer, and vasculitis (like Wegener granulomatosis) are examples of noninfectious causes of lung cavities.
Patients present with the usual symptoms of pulmonary infection, such as fever, cough, spu- tum production, and chest pain, plus the following:
Several weeks of weight loss, anemia, and fatigue often occur prior to diagnosis (likely due to the 1–2 week delay between the aspiration of oral contents and the development of necrosis and cavitation)
Diagnosis. Sputum for Gram stain and culture will not be able to show the causative anaerobic organism in a lung abscess. Chest x-ray in an abscess will often show a thick-walled cavitary lesion. Chest CT can help define the exact extent of the cavity. In the upright position the lower lobes are the most common sites of aspiration. In the supine position the posterior segment of the right upper lobe is the most common site. Aspiration of the abscess fluid is necessary for a specific bacteriologic diagnosis.
Treatment. In the absence of specific microbiologic diagnosis, clindamycin is good empiric coverage for the “above the diaphragm” anaerobes most often found. Penicillin is also acceptable.
In contrast to most abscesses where drainage is the rule, lung abscesses rarely require drainage in the antibiotic era. Most respond to antimicrobial therapy and drain spontaneously by communicating with larger bronchi. Therefore, the answer to the question, what is the best initial therapy for a lung abscess, is antibiotics such as clindamycin, not drainage.
Pneumonia
Pneumonia is an infection of the lung parenchyma. It is the 6th leading cause of death in the United States. It is not necessary to have a particular predisposing condition, although some conditions do predispose to having pneumonia: cigarette smoking, diabetes, alcoholism, malnutrition, obstruction of the bronchi from tumors, and immunosuppression in general. Neutropenia and steroid use predispose to Aspergillus infection.
The most common cause of community-acquired pneumonia in all groups is S. pneumoniae when an actual cause is identified (however, viruses are the most common cause in children age <5). Subsequent causes may vary, but S. pneumoniae is always number one. Hospital- acquired or ventilator-associated pneumonia shows a predominance of Gram-negative bacilli such as E. coli, the other Enterobacteriaceae, or Pseudomonas, as well as MRSA.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
238
Chapter 7 ● Infectious Diseases
Table 7-1. Frequency of Infectious Agents Causing Pneumonia
“Typical” | 40–60% |
Strep pneumoniae | 15–35% |
Haemophilus | 2–10% |
Moraxella | <5% |
“Atypical” | 10–30% |
Legionella | 0–15% |
Mycoplasma | 10% |
Chlamydia | 5–10% |
Viral | |
Unknown |
Specific predispositions are as follows:
Mycoplasma: young, otherwise healthy patients
Legionella: epidemic infection in older smokers, particularly when located near infected water sources, such as air-conditioning systems
Pneumocystis jiroveci (formerly carinii) pneumonia: HIV-positive persons with <200 CD4 cells not on prophylaxis
Coxiella burnetii (Q-fever): exposure to animals, particularly at the time they are giving birth
Klebsiella: alcoholics
Staphylococcus aureus: following viral syndromes or viral bronchitis, especially influenza
Coccidioidomycosis: exposure to the deserts of the American Southwest, particularly Arizona
Chlamydia psittaci: birds
Histoplasma capsulatum: exposure to bat or bird droppings, spelunking (recreational cave exploration)
Bordetella pertussis: cough with whoop and post-tussive vomiting
Francisella tularensis: hunters, or exposure to rabbits
SARS, Avian influenza: travel to Southeast Asia
Bacillus anthracis, Yersinia pestis, and Francisella tularensis: bioterrorism
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
239
USMLE Step 2 l Internal Medicine
Patients with pneumonia present with cough, fever, and often sputum production. Severe pneumonia of any cause may present with dyspnea. The quality and degree of sputum pro- duced might provide useful clues to the microbiologic etiology of pneumonia at the initial pre- sentation. Bacterial infections such as S. pneumoniae, Haemophilus, and Klebsiella have signifi- cant purulent sputum production because they are infections of the alveolar air space.
The sputum with S. pneumoniae is described as rusty. The “rust” is simply hemo- ptysis. As the blood oxidizes, it becomes brownish-red color. Any form of persistent cough may be associated with hemoptysis, however, and hemoptysis by itself is nonspecific.
The sputum with Klebsiella pneumoniae is described as currant jelly. This is simply hemoptysis with mucoid characteristics from a combination of the necrotizing nature of Klebsiella with the organism’s thick mucopolysaccharide coating.
Interstitial infections such as those caused by Pneumocystis pneumonia (PCP), viruses,
Mycoplasma, and sometimes Legionella often give a nonproductive or “dry” cough.
Any cause of pneumonia may be associated with pleuritic chest pain. This is pain worsened by inspiration. Commonly, pleuritic pain is associated with lobar pneumonia, such as that caused by Pneumococcus. This is because of localized inflammation of the pleura by the infection. Lobar pneumonia is the type most commonly associated with signs of consolidation on examination.
On physical examination pneumonia presents with rales, rhonchi, or signs of lung consolida- tion, including dullness to percussion, bronchial breath sounds, increased vocal fremitus, and egophony (E to A changes).
The respiratory rate is essential in determining the severity of a pneumonia. The respiratory rate is often a close correlate of the level of oxygenation. Severe pneumonia leads to hypoxia, which leads to hyperventilation.
Mycoplasma—Dry cough and chest soreness. Dyspnea is rare. Bullous myringitis and anemia from hemolysis from cold agglutinin disease are occasionally present. Patients with Mycoplasma pneumoniae rarely need to be admitted to the hospital; therefore, any patient presented to you as an inpatient is less likely to have Mycoplasma.
Legionella—CNS manifestations such as confusion, headache, and lethargy. GI mani- festations include diarrhea and abdominal pain.
PCP—Marked dyspnea, particularly on exertion, with chest soreness with cough in an HIV-positive person. Patients invariably have AIDS with a CD4 count of <200/μL.
Diagnosis. The most important initial test for any type of pneumonia is the chest x-ray. Besides being able to simply show the presence of disease, the chest x-ray gives the initial clue to determining the diagnosis. The most important initial clue to the diagnosis is whether the infiltrates are localized to a single lobe of the lung or whether they are bilateral and interstitial.
S. pneumoniae (and other causes of “typical” pneumonia) usually appear as a lobar pneumonia with parapneumonic pleural effusion. Interstitial infiltrates are associated with PCP, viral, Mycoplasma, Chlamydia, Coxiella, and sometimes Legionella pneumoniae. Sputum should be obtained for both Gram stain as well as culture. Sputum culture is the most specific diagnostic test for lobar pneumonia, such as with S. pneumoniae, Staphylococcus, Klebsiella, and Haemophilus. The other organisms (viral, Mycoplasma, Chlamydia, Coxiella, etc.), the so-called “atypical” organisms, will not show up on a Gram stain or regular bacterial culture for various reasons. Occasionally, more invasive tests are necessary to confirm the diagnosis such as
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
240
Chapter 7 ● Infectious Diseases
bronchoscopy, thoracentesis, pleural biopsy, or culture of pleural fluid. Ultimately, the most specific diagnostic test for pneumonia is with an open lung biopsy.
Organism-specific diagnostic methods are as follows:
Mycoplasma—Specific serologic antibody titers. Cold agglutinins have both limited specificity and sensitivity.
Legionella—Specialized culture media with charcoal yeast extract, urine antigen tests, direct fluorescent antibodies, and antibody titers.
PCP—Bronchoalveolar lavage, increased LDH
Chlamydia pneumoniae, Coxiella, Coccidioidomycoses, and Chlamydia psittaci—All of these are diagnosed with specific antibody titers.
Treatment. Treatment depends on whether the patient has a mild disease that can be treated as an outpatient or a more severe illness that must be treated with IV antibiotics as a hospital- ized inpatient. The major determinants of severity are the degree of hypoxia, such as a Po2 <60
mm Hg, oxygen saturation <94% on room air, or a respiratory rate >30/min; confusion or
disorientation; uremia; and hypotension (systolic BP <90 mm Hg and diastolic BP <60 mm Hg). Other markers of severity are high fever, hypothermia, leukopenia (WBC <4,000/mm3), rapid pulse (>125/min), hyponatremia, or dehydration as determined by an elevated BUN. Patients with serious underlying diseases such as cancer, liver disease, renal disease, or chronic lung disease often do better in hospital with IV medications.
The specific organism causing pneumonia is rarely, if ever, known at the time that the initial therapeutic decision must be made. Empiric therapy for pneumonia managed as an outpatient is with a macrolide, such as azithromycin or clarithromycin. This is because of the high frequency of Mycoplasma and Chlamydia pneumoniae as the cause of less severe community-acquired pneumo- nia (CAP). New fluoroquinolones (levofloxacin, moxifloxacin, or gemifloxacin) are alternatives.
Although oral second- and third-generation cephalosporins and amoxicillin/clavulanate are often used, they do not cover the atypical pathogens well.
Hospitalized patients with CAP should receive either levofloxacin, moxifloxacin, or gatifloxacin or a second- or third-generation cephalosporin such as cefotaxime or ceftriaxone combined with a macrolide antibiotic such as azithromycin or clarithromycin (or doxycy- cline).
Table 7-2. Empiric Therapy of Community-Acquired Pneumonia
Note
CURB-65 indicates need for hospitalization in pneumonia:
Confusion Uremia
Respiratory distress Blood pressure low Age >65
Outpatient (Nonhospitalized) | Inpatient (Hospitalized) |
First choice: macrolides: Azithromycin, clarithromycin Alternatives: new fluoroquinolones: Levofloxacin, moxifloxacin, gemifloxacin | New fluoroquinolones (levofloxacin, moxifloxacin, or gemifloxacin) or Second- or third-generation cephalosporins (cefuroxime or ceftriaxone) combined with a macrolide or doxycycline or Beta-lactam/beta-lactamase combination drug (ampicillin/sulbactam; ticarcillin/ clavulanate; piperacillin/tazobactam) combined with doxycycline or a macrolide |
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
241
USMLE Step 2 l Internal Medicine
Treatment of Hospital-Acquired Pneumonia. Those patients who develop pneumonia after 5–7 days in the hospital are at increased risk of infection from drug-resistant, Gram-negative bacilli (Pseudomonas, Klebsiella, E. coli, etc.) or gram-positive bacilli such as
methicillin-resistant Staphylococcus aureus (MRSA). Empiric therapy of hospital-acquired pneumonia is with third-generation cephalosporins with antipseudomonal activity (such as ceftazidime) or carbapenems (such as imipenem) or with beta-lactam/beta-lactamase inhibitor combinations (such as piperacillin/tazobactam) and coverage for MRSA with vancomycin or linezolid. Aminoglycosides (gentamicin, tobramycin, amikacin) are often added to empiric gram-negative coverage for synergy and to ensure that the patient might be getting at least one drug if the bacteria is multidrug resistant. Antibiotic therapy can then be adjusted when results of cultures (sputum, blood, bronchoalveolar lavage, and/or pleural) become available.
Treatment of specific organisms is as follows:
Haemophilus influenzae—Second- or third-generation cephalosporins
Pneumocystis pneumonia—Trimethoprim/Sulfamethoxazole (TMP/SMZ).
Steroids should be used if the infection is severe. Severe is defined as an arterial Po2
<70 mm Hg or an A-a gradient of >35 mm Hg. If the patient is allergic to TMP/SMZ,
Coxiella burnetii (Q-fever)—Doxycycline (or erythromycin as an alternative)
Klebsiella—Third-generation cephalosporins and the other drugs for Gram-negative bacilli
Staphylococcus aureus—Semisynthetic penicillins (oxacillin, nafcillin, etc.) if methicil- lin sensitive. In the nosocomial setting, isolates are invariably methicillin-resistant, and vancomycin or linezolid is administered.
Coccidioidomycosis—Primary pulmonary disease does not need to be treated. Treat- ment is only used for disseminated disease or in those with pulmonary disease who are immunosuppressed. Life-threatening disease is treated with amphotericin. Mild disease is treated with fluconazole or itraconazole.
Pneumococcal vaccine
Those patients at increased risk for pneumonia should receive pneumococcal vaccine. Those who should receive the vaccine include all patients age >65, as well as those with any serious underlying lung, cardiac, liver, or renal disease. Immunocompromised patients, such as those on steroids, HIV-positive persons, splenectomized patients, diabetics, and those with leukemia or lymphoma, should be vaccinated at the earliest possible opportunity. The vaccine is 60–70% effective. Re-dosing in 5 years is only necessary for those with severe immunocompromise or in those who were originally vaccinated before the age of 65. In generally healthy persons vaccinated age >65, a single dose of vaccine is enough to confer lifelong immunity.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
242
Chapter 7 ● Infectious Diseases
Tuberculosis
A 37-year-old resident of a maximum-security correctional facility has been having a cough, voluminous sputum production, and fever for the last few weeks. He has had a 10-pound weight loss and feels very weak.
Tuberculosis (TB) is an infection with Mycobacterium tuberculosis. Worldwide, TB is one of the top 3 causes of all deaths.
TB is spread exclusively by person-to-person transmission by means of respiratory droplet infection. There is no animal reservoir of the disease. Bacillus Calmette-Guérin (BCG) vaccination is used in many parts of the world outside the United States to try to prevent infection. It is, at best, 50% effective and is never indicated for routine use in the United States.
Besides immigrants, TB occurs predominantly in persons with specific risk for exposure, such as alcoholics, healthcare workers, prisoners, homeless shelter residents, nursing home residents, and chronically debilitated patients whose weakened immune systems allow for more frequent re-activation of latent infection. Impairment of T-cell–mediated cellular immunity is the most significant defect associated with re-activation. This is why steroid use, organ transplantation, leukemia, lymphoma, and HIV are such important risk factors.
Centers for Disease Control and Prevention
Figure 7-4. Tuberculosis X-ray
Patients present with cough, sputum, fever, and an abnormal lung exam. They may be impossible to distinguish clinically from those with pneumonia.
Weight loss is common because of the chronicity of the infection. Even when untreated, TB usually takes up to 5 years to become fatal.
Night sweats may occur.
TB can occur outside the lungs (15–20% of cases).
Note
Nearly 25% of the world’s population has been exposed to TB and would be reactive to PPD testing. Until the middle of this century, TB was the most common cause of death in the United States, but it is now at an all-time low, with
<15,000 cases per year (over half of those are recent immigrants).
Note
Lymph node involvement (adenitis) is the most frequently involved extrapulmonary site in TB.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
243
USMLE Step 2 l Internal Medicine
Clinical Pearl
Newer tests may provide TB sensitivity testing in a few weeks, thus the period of using 4 drugs is significantly shortened.
Presentation depends on site involved
Any part of the body can be involved
In extrapulmonary TB, the lymph node (adenitis), meningeal, GI, and GU are most commonly seen
Diagnosis. Chest x-ray is the best initial test, as it is with all forms of pulmonary infection. Apical involvement with infiltrates and sometimes cavitation is the most common finding. Adenopathy, effusion, and calcified nodules (Ghon complex) are associated findings.
Sputum examination with specific staining for acid-fast bacilli (AFB) allows specific diagnosis. AFB stain has limited sensitivity, and you need 3 negative smears to reach
>90% sensitivity. AFB-positive sputum staining is usually the trigger to start therapy for TB.
Culture is the most specific test, but because it takes 4–6 weeks to grow it is not often available to guide initial therapy. The culture is also necessary in order to do sensitiv- ity testing.
Pleural biopsy is the single most sensitive diagnostic test. A single pleural biopsy can have up to 75% sensitivity. TB will give caseating necrosis on biopsy of any tissue.
Do not use PPD testing to diagnose acute cases of TB. PPD is relatively insensitive and nonspecific particularly with acute illness.
Treatment. Initial therapy of TB before the results of sensitivity testing are known consists of 4-drug therapy with isoniazid (INH), rifampin (Rif), pyrazinamide (PZA), and ethambutol (ETB). All 4 drugs are continued for the first 2 months or until sensitivity testing is known. PZA and ETB are then discontinued, and therapy continues with INH and rifampin for another 4 months. This makes routine therapy last for a total of 6 months. The fourth drug, ETB, is given if the sensitivity is not known. The only forms of TB that definitely must be treated for longer than 6 months are TB meningitis (12 months), TB in pregnancy (9 months), and osteomyelitis. HIV-positive persons may be treated for 6–9 months, but there is no clear evidence that 9 months is necessary, i.e., even in HIV-positive persons, 6 months of therapy is effective. INH use should generally be combined with vitamin B6 (pyridoxine) to prevent peripheral neuropathy that can be a side effect of INH.
Pregnant patients should not receive PZA or streptomycin. Steroid use with TB medications is only your answer for TB meningitis and TB pericarditis.
All of the TB medications can cause liver toxicity, except streptomycin. INH also causes peripheral neuropathy because of pyridoxine deficiency. Rifampin is associated with causing a benign change in the color of all bodily fluids to orange/red. This color is dangerous only because it could stain contact lenses and white underwear. Ethambutol is associated with optic neuritis, which can cause color blindness and other visual disturbances. PZA can cause a benign hyperuricemia. Don’t treat the hyperuricemia unless there are symptoms of gout associated with it, which rarely occurs.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
244
Chapter 7 ● Infectious Diseases
Diagnosis and Treatment of Latent TB Infection. The PPD test and interferon gamma release assay (IGRA) are used to screen asymptomatic populations at risk of TB to see if they have been exposed and are at increased risk of re-activating the disease. The AFB stain and culture of the affected tissues should be performed. PPD is considered positive based on the amount of induration of the skin 48–72 h after the intradermal (not subcutaneous) injection of the PPD. Erythema is irrelevant. A positive PPD or IGRA roughly indicates a 10% lifetime risk of develop- ing TB in HIV-negative persons. Most of the active cases will develop within the first 2 years after converting to a positive test. HIV-positive persons have a roughly 7–10% risk per year of developing active disease. Previous BCG vaccination does not alter these recommendations. The cutoffs are as follows:
≥5 mm:
Close contacts of active TB cases
HIV-positive persons
Steroid use or organ transplantation recipients
≥15 mm: Low-risk populations, i.e., not the people described, i.e., people who should never have been tested in the first place.
Two-Stage Testing: Those in whom there has not been a recent PPD test and now show some reactivity that is <10 mm should have a second test within 2 weeks. This is to make sure the first test was not a false negative. A reaction of >10 mm on the second test is simply a positive test, not a recent converter. You cannot make a PPD-negative person become positive with repeated testings.
All patients who test positive on the PPD test or IGRA should have a chest x-ray to see if they have early asymptomatic evidence of TB on their film. Those with abnormal chest x-rays should have 3 sputum AFB stains done to see if they have active disease. Positive AFB smears indicate the need for the start of 4 TB drugs as described.
Patients with positive PPD tests or IGRA and no evidence of active disease should receive therapy with 9 months of INH and vitamin B6. A normal chest x-ray or an abnormal x-ray and 3 negative AFB stains of sputum are sufficient to exclude active disease. Although 6 months of INH/B6 is an acceptable alternative, the recommendation is that all patients, including those who are HIV positive, should receive the same 9-month course of therapy. Previously, this was referred to as “prophylaxis.” The proper designation is now “treatment of latent TB.”
The IGRA is not altered at all with previous BCG vaccine. The IGRA has the same meaning and treatment as a positive PPD skin test. Previous BCG vaccination does not alter these recommendations in any way. Previous BCG will not make the IGRA positive.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
245
USMLE Step 2 l Internal Medicine
Clinical Recall
Which of the following is not an indication for hospitalization in patients with pneumonia?
PO2 of 50 mm Hg
Creatinine of 2.5 mg/dL
Temperature of 104 F
Leukocytosis of 11,000
Underlying COPD
Answer: D
Infectious Diarrhea/Food Poisoning
A 27-year-old medical student leaves the Step 2 class at 12:30 to go to lunch. At 3 p.m. she starts having repeated episodes of diarrhea. The diarrhea contains blood and mucus. She is also febrile and has abdominal pain.
Most infectious diarrhea is caused by contaminated food and water, so the overlap between infectious diarrhea and food poisoning is considerable. There are several types of food poisoning, such as Bacillus cereus and Staphylococcus aureus, which present predominantly with vomiting, so the two terms are not entirely synonymous.
A wide variety of agents can cause food poisoning.
Salmonella (most commonly associated agent with contaminated poultry and eggs)
E. coli (most common cause of travelers’ diarrhea; produces a wide spectrum of disease depending on whether it makes toxin or is invasive)
E. coli 0157:H7 is associated with undercooked hamburger meat.
Bacillus cereus is associated with fried rice; the rice becomes contaminated with bacillus spores, and as it is prepared for serving it is warmed only at a moderate temperature not hot enough to kill the spore.
Giardia lamblia and cryptosporidiosis are acquired from contaminated water sources that have not been appropriately filtered, such as fresh water on a camping trip. Cryptosporidiosis is also associated with HIV, particularly when there is profound immunosuppression and CD4 <50 cells.
There are several types of Vibrio causing human disease.
V. cholera (very rare in the United States)
V. parahaemolyticus (associated with ingestion of contaminated shellfish such as clams and mussels)
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
246
Chapter 7 ● Infectious Diseases
– V. vulnificus (associated with ingestion of raw shellfish); causes severe disease in those with underlying liver disease; also associated with iron overload and the development of bullous skin lesions
Viral infections such as rotavirus or Norwalk agents are most commonly associated with outbreaks in children.
Clostridia associations are as follows:
C. difficile with previous antibiotic use
C. botulinum with ingestion of infected canned foods
C. perfringens with ingestion of meat contaminated with spores due to unre- frigeration
Although it is important to be familiar with these associations, remember that virtually any food can be contaminated by almost any organism. The most important thing is not what food you eat but whose dirty hands touched your food and what were they contaminated with.
Clinical Presentation. The most important feature of any person presenting with possible food poisoning is the presence or absence of blood in the stool. Blood is most commonly associated with invasive enteric pathogens, such as Salmonella, Shigella, Yersinia, invasive
coli, and Campylobacter. The time between the development of the diarrhea from the ingestion of the food is not as important as the presence of blood. Incubation times are helpful only if you have a group outbreak and you can pinpoint a common source of contamination. In other words, the last thing you eat is not necessarily the thing that was contaminated. The invasive enteric pathogen may be causing infection in the absence of blood, however, and the absence of blood does not exclude them. Campylobacter is rarely associated with Guillain-Barré syndrome.
Ingestion of ciguatera toxin causes symptoms within 2–6 hours, which includes paresthesias, numbness, nausea, vomiting, and abdominal cramps. In severe cases symptoms can be neurologic (weakness, reversal of hot-cold sensations), and cardiovascular (hypotension).
Neurologic symptoms can be severe, progressive, and debilitating.
There is no specific therapy to reverse ciguatera poisoning. The most commonly implicated fish are barracuda, red snapper, and grouper.
E. coli 0157:H7 and Shigella are associated with hemolytic uremic syndrome (HUS).
Bacillus cereus and Staphylococcus predominantly present with vomiting within
1–6 hours of their ingestion because they contain a preformed toxin. They can cause diarrhea later.
Giardia, Cryptosporidium, Cyclospora, and most other protozoans do not cause bloody diarrhea. The major protozoan associated with blood in the stool is Entamoeba histolytica.
Viruses can give voluminous watery diarrhea but do not cause bloody diarrhea.
Scombroid is a type of poisoning that occurs after ingestion of scombroid fish (tuna, mackerel, mahi mahi), which may contain a lot of histamine. When ingested, scombroid can give symptoms within a few minutes: rash, diarrhea, vomiting, and wheezing, along with a burning sensation in the mouth, dizziness, and paresthesias.
Diagnosis. When there is no blood present in the stool, determine the etiology of the diarrhea via a stool test for the presence of WBCs with methylene blue testing. WBCs will indicate that there is an invasive pathogen, but only a culture will identify the specific type.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
247
USMLE Step 2 l Internal Medicine
Giardia and Cryptosporidia are detected by direct examination of the stool for the parasites, as well as for their eggs. A special modified AFB stain is necessary to detect Cryptosporidia. Stool ELISA is also used for Giardia.
Treatment. Therapy is determined by the severity of disease. Mild infections with the invasive pathogens and viruses usually require only oral fluid and electrolyte replacement. More severe infections, such as those producing high fever, abdominal pain, tachycardia, and hypotension, require IV fluids and oral antibiotics.
You rarely, if ever, have the luxury of knowing the specific etiology when the initial therapeutic decision must be made. The best initial empiric antibiotic therapy of an invasive pathogen is a fluoroquinolone, e.g., ciprofloxacin.
Organism-specific therapy is as follows:
Campylobacter: erythromycin
Cryptosporidium: control of underlying HIV disease with antiretrovirals, nitazoxanide
Nitazoxanide is the first truly useful therapy for cryptosporidiosis.
Scombroid: antihistamines such as diphenhydramine
ACUTE VIRAL HEPATIC INFECTIONS
An 18-year-old woman comes to the emergency department because of several days of nausea, vomiting, and fever. She uses no medications. She reports unprotected sex. Her stool is light in color. On physical examination she is jaundiced.
Viral hepatitis is an infection of the liver caused by hepatitis A, B, C, D, or E.
Hepatitis A and E are transmitted by contaminated food and water. They are orally ingested and have an asymptomatic incubation period of several weeks, with an average of 2–6 weeks. They cause symptomatic disease for several days to weeks, have no chronic form, and do not lead to either cirrhosis or hepatocellular carcinoma.
Hepatitis B, C, and D are transmitted by the parenteral route. They can be acquired perinatally or through sexual contact, blood transfusion, needlestick, and needle sharing.
Hepatitis G has been identified in a small number of patients through screening of the blood supply but has not yet been associated with clinical disease.
Hepatitis B and C can lead to a chronic form, which can cause cirrhosis and hepato- cellular carcinoma. Four million people in the United States are infected with hepati- tis C. Hepatitis C is the most common disease leading to the need for liver transplantation in the United States.
All forms can occasionally present with fulminant hepatic necrosis and acute liver failure.
The most common presentation of acute hepatitis of any cause is jaundice, dark urine, light- colored stool, fatigue, malaise, weight loss, and a tender liver. On physical examination the liver may be enlarged.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
248
Chapter 7 ● Infectious Diseases
You cannot distinguish the precise viral etiology of the hepatitis by initial presentation alone. In fact, drug-induced hepatitis, i.e., that from isoniazid or massive alcohol use, may present with the same symptoms. Hepatitis B and C can also produce symptoms similar to serum sickness, such as joint pain, rash, vasculitis, and glomerulonephritis. They also lead to cryo- globulinemia. Hepatitis B has been associated with the development of polyarteritis nodosa (PAN). Hepatitis E has been associated with a more severe presentation in pregnant women.
Table 7-3. Comparative Features: Hepatitis A, B, C, E, and Delta
Feature | Hepatitis A | Hepatitis B | Hepatitis C | Delta | Hepatitis E |
Incubation period (wk) | 2–6 (avg. 4) | 4–26 (avg. 13) | 2–20 | 4–8 | — |
Transmission | Fecal-oral | Sexual > | Parenteral > sexu- al | Parenteral, sexual | Fecal-oral |
Severity | Mild | Co-infection with B | Mild, except in pregnant women | ||
Fulminant hepatitis | Rare | Co-infection occasional | Rare | ||
Symptoms | Fever, malaise, headache, anorexia, vomiting, dark urine, jaundice | As with A | As with A | ||
Carrier state | None | None | |||
Chronicity (%) | 0 | 0 | |||
Associated with blood transfusion (%) | Occurs, but frequency unknown | Rare | |||
Serology | Anti-HAV IgM fraction IgG fraction | HBsAg, HBsAb HBeAg Anti-HBs Anti-HBc Anti-HBe | Antibody to hepatitis C PCR-RNA | Anti-delta IgM fraction IgG fraction | Anti-Hep E IgM IgG |
Postexposure prophylaxis | Immunoglobin Hep A vaccine | HBIg/Hep B vaccine | None effective | None | Unknown |
Association with cirrhosis | No | Yes | Yes | Yes | No |
Association with primary hepatocellular carcinoma | No | Yes | Yes | Yes | No |
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
249
USMLE Step 2 l Internal Medicine
Note
For the treatment of
hepatitis B, entecavir, adefovir, tenofovir, and telbivudine can be used in place of lamivudine.
Diagnosis. All forms of viral and drug-induced hepatitis will produce elevated total and direct bilirubin levels.
Viral hepatitis will produce both elevated ALT and AST, but ALT is usually greater than the AST.
With drug- and alcohol-induced hepatitis, AST is usually more elevated than the ALT.
Alkaline phosphatase and GGTP are less often elevated because these enzymes usually indicate damage to the bile canalicular system or obstruction of the biliary system.
If there is very severe damage to the liver, prothrombin time and albumin levels will be abnormal.
Hepatitis A, C, D, and E are diagnosed as acute by the presence of the IgM antibody to each of these specific viruses. IgG antibody to hepatitis A, C, D, and E indicates old, resolved dis- ease.
Hepatitis C activity can be followed with PCR-RNA viral load level. However, do not use PCR to establish the initial diagnosis.
Hepatitis B is diagnosed as acute with the presence of the hepatitis B surface antigen, which is the first viral marker to elevate. The hepatitis B e antigen and IgM core antibody also help establish acute infection.
The e antigen indicates high levels of viral replication and is a marker for greatly increased infectivity.
Treatment. There is no effective therapy for acute hepatitis B. Chronic hepatitis B can be treated with interferon, entecavir, adefovir, or lamivudine.
With the approval of the newest hepatitis C drugs, the goal of HCV treatment is to cure the virus, which can be done with a combination of drugs. The specific medications used and the duration of treatment depend on a number of factors:
HCV genotype
Viral load
Past treatment experience
Degree of liver damage
Ability to tolerate the prescribed treatment
Whether patient is waiting for a liver transplant or is transplant recipient
There are a number of approved therapies to treat HCV, such as sofosbuvir/ledipasvir, simepre- vir, sofosbuvir, and Viekira Pak (ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir tablets that may be prescribed with or without ribavirin). Simeprevir and sofosbuvir can be prescribed together with or without ribavirin, or each may be separately combined with ribavirin and in some cases peginterferon as well.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
250
Chapter 7 ● Infectious Diseases
Sofosbuvir/ledipasvir, the current preferred HCV treatment, is 2 drugs formulated in to one daily pill. For genotype 1 success rates of sofosbuvir/ledipasvir are around 94–99%, while treatment duration is 8–12 weeks. Both are direct-acting antivirals (DAAs) which means they directly interfere with hepatitis C virus replication. Sofosbuvir is a polymerase inhibitor while ledipasvir, an NS5A inhibitor. Patients who have never been treated for HCV—whether they have cirrhosis or not—take sofosbuvir/ledipasvir for 12 weeks. Treatment-naïve patients without cirrhosis whose pre-treatment viral load (HCV RNA) is <6 million IU/mL may be considered for 8 weeks of treatment.
When hepatitis C treatment is working, the virus will become undetectable within 4–12 weeks and will remain that way throughout treatment. Patients are considered cured when they have achieved what is known as a sustained virologic response (SVR), or continuation of this undetectable status, 12–24 weeks after completing therapy.
After a needlestick from a hepatitis B surface-antigen—positive patient, the person stuck should receive hepatitis B immunoglobulin (HBIg) and hepatitis B vaccine. If the person stuck already has protective levels of surface antibody to hepatitis B present in the blood, then no further therapy is indicated. There is no effective postexposure prophylaxis to hepatitis C, and there is no vaccine. All healthcare workers, IV drug users, and others at risk should be vaccinated for hepatitis B. All newborn children are vaccinated against hepatitis B and A. Hepatitis A vaccine should be given to those traveling to countries that may have contaminated food and water, those with chronic liver disease, and those with high risk sexual behavior.
Clinical Recall
Which of the following Hepatitis B markers indicates a high level of infectivity?
HBsAg
HBeAg
HBcAg
HBcAg IgM
HBcAg IgG
Answer: B
GENITAL AND SEXUALLY TRANSMITTED INFECTIONS
Urethritis
A 31-year-old man is in your clinic today with several days of urinary frequency, urgency, and burning.
Urethritis is inflammation of the urethra.
Gonococcal urethritis caused by Neisseria gonorrhoeae
Nongonococcal urethritis caused by either Chlamydia trachomatis (50%), Ureaplasma urealyticuUmS(M2L0E%®), iMs aycjoopinlatspmroagrhaommoinfiTsh(e5%Fe)d, eTrraitcihoonmoofnSataste(1M%e),dhicearlpBeos asridmspolefxthe United States, Inc.
and the National Board of Medical Examiners.
251
USMLE Step 2 l Internal Medicine
Patients present with purulent urethral discharge; dysuria, urgency, and frequency in urination.
Smear can show the Gram-negative, coffee bean–shaped diplococci intracellularly. Serology (fluorescent antibodies) for chlamydia by swabbing the urethra, or by ligase chain reaction test of voided urine. Culture for gonorrhea is the most specific test for gonorrhea.
Treatment. Single-dose ceftriaxone intramusculary and single-dose azithromycin orally is now the treatment of choice. An alternative regimen with doxycycline for 7 days can also be used. Gonorrhea can also be treated with single-dose cefixime. This is the same treatment as that for cervicitis. Ciprofloxacin should not be used as first-line therapy for gonorrhea.
Pelvic Inflammatory Disease
Pelvic inflammatory disease (PID) describes a group of infections involving the fallopian tubes, uterus, ovaries, or ligaments of the uterus. The etiology is N. gonorrhoeae, Chlamydia, Mycoplasma, anaerobic bacteria, or Gram-negative bacteria. Intrauterine devices predispose to PID.
Clinical findings include lower abdominal and pelvic pain on palpation of the cervix, uterus, or adnexa; fever, leukocytosis, and discharge are common. Cervical motion tenderness is key. Discharge from the cervix may be present.
To diagnose, do culture on Thayer-Martin for gonococcus and Gram stain of discharge, increased ESR.
If there is fluid in the retrouterine cul-de-sac, a culdocentesis is performed (rare).
Ultrasonography of the pelvis may help to exclude other pathology, such as an ovarian cyst or tubo-ovarian abscess.
Clinical presentation is the main method (CMT/adnexal tenderness).
Treatment. Doxycycline and cefoxitin (or cefotetan) for inpatient therapy. Outpatient therapy is with single-dose ceftriaxone intramuscularly and doxycycline orally for 2 weeks. The main reason to treat in hospital is a high WBC or high fever. Outpatient therapy can also be with 2 weeks of oral ofloxacin and metronidazole as a second-line agent.
Complications of PID include infertility and ectopic pregnancy.
Syphilis
A 43-year-old man comes to the clinic with several days of an ulcerated genital lesion. He also has some surrounding adenopathy.
Syphilis is a systemic contagious disease caused by a spirochete; characterized by periods of active manifestations and by periods of symptomless latency. It is caused by Treponema pallidum.
Syphilis can be classified as being congenital or acquired.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
252
Chapter 7 ● Infectious Diseases
Congenital
Early: symptomatic; seen in infants up to age 2
Late: symptomatic, Hutchinson teeth, scars of interstitial keratitis, bony abnormalities (saber shins)
Acquired
Early infectious syphilis
Primary stage: chancre appears by week 3 and disappears in 10–90 days; also, regional lymphadenopathy is painless, rubbery, discrete, and nontender to palpa- tion (primary chancres are found on penis, anus, rectum [men], and vulva/cervix/ perineum [women] but may appear on lips, tongue, etc.)
Latent stage: asymptomatic; may persist for life; 35% of patients develop late or tertiary syphilis
Late or tertiary syphilis: most commonly neurologic
Centers for Disease Control and Prevention, M. Rein, VD
Figure 7-5. Syphilis, Primary Chancre
.Patients are symptomatic but not contagious.
Benign tertiary syphilis develops 3–20 years after the initial infection; typical lesion is the gumma (a chronic granulomatous reaction) found in any tissue or organ, which will heal spontaneously and leave a scar
Cardiovascular syphilis and neurosyphilis are the other manifestations of tertiary syphilis. The Argyll Robertson pupil (usually only with neurosyphilis) is a small irregular pupil that reacts normally to accommodation but not to light. Tabes dorsalis (locomotor ataxia) results in pain, ataxia, sensory changes, and loss of tendon reflexes. Neurosyphilis is rare and is essentially the only significant manifestation of tertiary syphilis likely to be seen. The FTA on CSF is far more sensitive for neurosyphilis than a VDRL.
Note
Use the FTA to exclude neurosyphilis in CSF.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
253
USMLE Step 2 l Internal Medicine
Centers for Disease Control and Prevention
Figure 7-6. Syphilis, Secondary Palms
Diagnosis. Screening tests are the VDRL and RPR; specific tests are the FTA-ABS, MHA-TP, and Darkfield exam of chancre. There can be false–positives VDRL with EBV, collagen vascular disease, TB, and subacute bacterial endocarditis.
Treatment. Penicillin is the drug of choice for all stages of syphilis. A reaction called Jarisch- Herxheimer can occur in >50% of patients (general malaise, fever, headache, sweating rigors, and temporary exacerbations of the syphilitic lesions 6–12 hours after initial treatment).
Tertiary syphilis is treated with penicillin 10–20 million units/day IV for 10 days.
Penicillin-allergic patients receive doxycycline for primary and secondary syphilis, but must be desensitized in tertiary syphilis. Pregnant patients must also undergo desensitization.
Chancroid
Chancroid is an acute, localized, contagious disease characterized by painful genital ulcers and suppuration of the inguinal lymph nodes. It is caused by Haemophilus ducreyi (Gram-negative bacillus).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
254
Chapter 7 ● Infectious Diseases
Centers for Disease Control and Prevention
Patients present with small, soft, painful papules that become shallow ulcers with ragged edges. They vary in size and coalesce. Inguinal lymph nodes become very tender and enlarged.
Diagnosis is made on clinical findings; do a Gram stain initially with culture to confirm. PCR testing is useful. Treatment is azithromycin single dose or ceftriaxone intramuscularly (single dose). Alternatives include erythromycin for 7 days or ciprofloxacin for 3 days.
Lymphogranuloma venereum is a contagious, sexually transmitted disease having a transitory primary lesion followed by suppurative lymphangitis. It is caused by Chlamydia trachomatis.
Clinical findings include the following:
Small, transient, nonindurated lesion that ulcerates and heals quickly
Unilateral enlargement of inguinal lymph nodes (tender)
Multiple draining sinuses (buboes) that develop (purulent or bloodstained)
Scar formation, persistent sinuses; fever, malaise, joint pains, and headaches (all common)
Diagnosis is made by clinical examination, history, and a high or rising titer of complement fixing antibodies. Isolate chlamydia from pus in buboes. Treat with doxycycline or erythromycin.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
255
USMLE Step 2 l Internal Medicine
Wikimedia, Herbert L. Fred, MD, and Hendrik A. van Dijk
Figure 7-8. Lymphogranuloma Venereum
Granuloma inguinale is a chronic granulomatous condition, probably spread by sexual contact. It is caused by Donovania granulomatis Calymmatobacterium granulomatis.
A painless, red nodule will develop into an elevated granulomatous mass. In men, it is seen on the penis, scrotum, groin, and thighs. (In homosexual men, the anus and buttocks are com- mon areas.) In women it is found on the vulva, vagina, and perineum.
Healing is slow, and there is scar formation. It looks like condyloma lata or carcinoma.
Diagnosis is made clinically and by performing a Giemsa or Wright stain (Donovan bodies) or smear of lesion. Also do punch biopsy. Treat with doxycycline, ceftriaxone, or TMP/SMZ. Erythromycin is an alternative.
phil.cdc.gov
Figure 7-9. Lesions of Granuloma Inguinale Due to
Calymmatobacterium Granulomatis Infection
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
256
Chapter 7 ● Infectious Diseases
Genital Herpes
Genital herpes is generally the herpes virus type II, although type I may be seen. Vesicles develop on the skin or mucous membranes; they become eroded and painful and present with circular ulcers with a red areola. Itching and soreness usually precede them. Lesions are commonly seen on the penis (men) and on the labia, clitoris, perineum, vagina, and cervix (women).
The ulcers are scarring and there can be inguinal lymphadenopathy.
Diagnosis is made with the Tzanck test and culture. Treat with oral acyclovir, famciclovir, or valacyclovir. Make sure to educate the patient about the relapsing nature of the disease. Those with frequent recurrence should be given chronic suppressive therapy.
Genital Warts
Genital warts are also known as condylomata acuminata or venereal warts. They are caused by the papilloma virus.
Genital warts are commonly found on warm, moist surfaces in the genital areas. They appear as soft, moist, minute, pink, or red swellings which grow rapidly and become pedunculated. Their cauliflower appearance makes them unique in appearance.
Diagnosis is made by clinical appearance. Differentiation must be made between flat warts and condylomata lata of secondary syphilis. Treatment includes the following:
Destruction (curettage, sclerotherapy, trichloroacetic acid)
Cryotherapy
Podophyllin
Laser removal
Clinical Recall
Which of the following is the treatment of choice for tertiary syphilis?
IM penicillin G x 1 dose
PO doxycycline x 14 days
IV penicillin G x 10 days
Doxycycline x 28 days
IV ceftriaxone x 1 day
Answer: C
Clinical Correlate Transmission of genital herpes commonly occurs during an
asymptomatic phase, when a
person who is shedding the virus inoculates virus onto a mucosal surface of the sexual partner.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
257
USMLE Step 2 l Internal Medicine
URINARY TRACT INFECTIONS
Cystitis
A 32-year-old woman is in your office because of dysuria. For the last several days, she has burning on urination with increased frequency and urgency to urinate.
Cystitis is infection of the urinary bladder. It is very common, mostly in women. In the United States, it causes 6 million office visits each year.
Etiology.
Roughly the same as for pyelonephritis
Tumors/stones/strictures/prostatic hypertrophy/neurogenic bladder
Catheters are a major cause, and the risk is directly related to the length of catheter- ization (3–5% per day).
Microbiology: E. coli in >80%; second are other coliforms (Gram-negative bacilli) such as Proteus, Klebsiella, Enterobacter, etc.; enterococci occasionally, and Staph. sapro- phyticus in young women.
Common presenting symptoms include dysuria, frequency, urgency, and suprapubic pain. Less common symptoms include hematuria, low-grade fever; foul-smelling and cloudy urine. On exam, there is suprapubic tenderness but no flank tenderness.
Best initial test is the urinalysis looking for WBCs, RBCs, protein, and bacteria; WBCs is the most important.
Urine culture with >100,000 colonies of bacteria per mL of urine confirmatory but not always necessary with characteristic symptoms and a positive urinalysis.
Treatment
For uncomplicated cystitis, 3 days of trimethoprim/sulfamethoxazole, nitrofurantoin, or any quinolone
Seven days of therapy for cystitis in diabetes
Quinolones should be avoided in pregnancy.
Fosfomycin is single-dose oral therapy for cystitis only
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
258
Chapter 7 ● Infectious Diseases
Acute Bacterial Pyelonephritis
Acute bacterial pyelonephritis is an acute patchy, most often unilateral, pyogenic infection of the kidney. Infection usually occurs by ascension after entering the urethral meatus.
Predisposing factors include obstruction due to strictures, tumors, calculi, prostatic hypertrophy, or neurogenic bladder, vesicoureteral reflux
Women > men
More common in childhood, during pregnancy, or after urethral catheterization or instrumentation
E. coli is most common pathogen; others include Klebsiella, Proteus, and Enterococcus
Patients who are immunosuppressed and subjected to indwelling catheters are more prone to Candida.
Pathology shows polymorphonuclear neutrophils and leukocytes (in interstitial tissue and lumina of tubules). Clinical findings include chills, fever, flank pain, nausea, vomiting, costovertebral angle tenderness, increased frequency in urination, and dysuria.
Diagnose with dysuria and flank pain. Confirm with clean-catch urine for urinalysis, culture, and sensitivity. In the majority of cases, >100,000 bacteria/mL of urine.
Routine imaging is not required, but if there is no improvement in 48–72 hours or complica- tions are suspected (obstruction, renal, or perinephric abscess), consider U/S or CT.
Treatment. Antibiotics for 10–14 days (fluoroquinolone), or ampicillin and gentamicin, or a third-generation cephalosporin are all acceptable. Essentially, any of the antibiotics for Gram-negative bacilli are effective.
Most patients can be treated as outpatients, though pregnant women who appear very ill and those unable to tolerate oral medication due to nausea or vomiting should initially be hospital- ized. Because of increasing resistance to TMP/SMZ, which has approached almost 20% in some parts of the United States, this agent is no longer recommended for empiric therapy until culture results and antibiotic sensitivity results are available.
Perinephric Abscess
Perinephric abscess is a collection of infected material surrounding the kidney and generally contained within the surrounding Gerota fascia. It is very uncommon. Although any factor predis- posing to pyelonephritis is contributory, stones are the most important and are present in 20–60%. Other structural abnormalities, recent surgery, trauma, and diabetes are also important.
Pathophysiology
Arises from contiguous pyelonephritis that has formed a renal abscess
Rupture occurs through the cortex into the perinephric space
Microbiology: 1) The same coliforms as in cystitis and pyelonephritis; 2) E. coli most common, then Klebsiella, Proteus; 3) Staph. aureus sometimes accounts for hematog- enous cases
Signs and Symptoms
Often insidious; 2–3 weeks of symptoms prior to first physician visit
Fever is the most common symptom
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
259
USMLE Step 2 l Internal Medicine
Note
Injection drug use is a significant risk factor for vertebral osteomyelitis in adults.
Flank pain/palpable abdominal mass/abdominal pain
Persistence of pyelonephritis-like symptoms despite treatment for pyelonephritis
The best initial tests are urinalysis (normal 30%) and urine culture (normal 40%). Fever and pyuria with negative urine culture or polymicrobial urine culture are suggestive.
Imaging is essential; U/S is the best initial scan but CT or MRI scan offers better imaging. Aspiration of the abscess is needed for definitive bacteriologic diagnosis.
Treatment.
Antibiotics for Gram-negative rods
Third-generation cephalosporins, antipseudomonal penicillin, or ticarcillin/clavula- nate, often in combination with an aminoglycoside, for example
Antibiotics alone are unlikely to be successful. Drainage (usually percutaneous) is necessary.
Osteomyelitis is an infection of any portion of the bone including marrow, cortex, and perios- teum. There are 3 types:
Acute hematogenous occurs mostly in children in the long bones of the lower extremities and is secondary to a single organism 95% of the time. The most common organism is Staphylococcus aureus. The most commonly involved bones are the tibia and femur, and the location is usually metaphyseal due to the anatomy of the blood vessels and endothelial lining at the metaphysis. In adults, hematogenous osteomyelitis accounts for about 20% of all cases and the most common site is the vertebral bodies (lumbar vertebrae are most frequently involved). The infection can extend posteriorly to form an epidural abscess. A patient with this diagnosis would present with fever and back tenderness.
Secondary to contiguous infection can occur in anyone with recent trauma to an area or placement of a prosthetic joint. Although this is secondary to a single organ- ism most of the time, a higher percentage is polymicrobial in origin.
aureus is the most common organism.
Vascular insufficiency is mostly seen age >50, with diabetes or peripheral vascular disease, resulting in repeated minor trauma that is not noticed because of neuropathy and decreased sensation. It is most common in small bones of the lower extremities. The majority is polymicrobial, but the single most common organism is still S. aureus.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
260
Chapter 7 ● Infectious Diseases
Presentation. Pain, erythema, swelling, and tenderness over the infected bone. With vascular insufficiency, there is often an obvious overlying or nearby ulceration or wound. Occasionally, a draining sinus tract is present.
Diagnosis. The earliest tests to detect osteomyelitis are the technetium bone scan and the MRI. Both have equal sensitivity for early pick-up, but the MRI can allow better differentiation between the overlying soft-tissue infection and bone. The MRI can be less readily available, however.
Plain x-ray: Usually the initial test because it is more easily obtained, easily read, and inexpensive. Periosteal elevation is the first abnormality visible. The disadvantage is that 50–75% of bone calcification must be lost before the bone itself appears abnormal, which usually takes at least 2 weeks to develop.
Erythrocyte sedimentation rate (ESR): Nonspecific. It is useful to follow during treatment. A normal value strongly points away from osteomyelitis.
Bone biopsy and culture: This is the best diagnostic test but also the most invasive.
CT scan, indium, and gallium: All 3 can be abnormal in osteomyelitis, but none are as specific or sensitive as the tests listed above.
Treatment. Acute hematogenous osteomyelitis in children can usually be treated with antibiotics alone; however, osteomyelitis in adults requires a combination of surgical (wound drainage and debridement, removal of infected hardware) and antibiotic therapy. Antibiotic therapy depends on the specific isolate obtained, which must be as precise as possible because empiric treatment for 6–12 weeks would be undesirable. A semisynthetic penicillin (oxacillin, nafcillin) or vancomycin (if MRSA is suspected) plus an aminoglycoside or a third-generation cephalosporin would be adequate until a specific diagnosis is obtained. Chronic osteomyelitis must be treated for as long as 12 weeks of antibiotic therapy, and in some cases, even longer periods of antibiotics may be required. The other MRSA drugs are daptomycin, linezolid, ceftaroline, and tigecycline.
Septic Arthritis
Septic arthritis is an infection of a joint due to virtually any agent. The most common etiology is bacterial; specifically, Neisseria gonorrhoeae, staphylococci or streptococci, but Rickettsia, viruses, spirochetes, etc., may also cause it. Generally, bacterial arthritis is divided into gonococcal and nongonococcal types.
Pathogenesis. Sexual activity is the only significant risk factor for gonococcal septic arthritis. A total of 1–5% of people with gonorrhea will develop disseminated disease, and 25% will have a history of recent symptomatic gonorrhea. Nongonococcal bacterial arthritis is usually spread by the hematogenous route. Additional routes may include bites (animal or human), direct inocula- tion of bacteria into the joint through surgery or trauma, or spread of infection from surround- ing structures such as bone. Even though both normal or damaged joints can get infected, any previous damage to a joint, such as from rheumatoid arthritis or osteoarthritis, previous surgery, prothesis placement, gout, sickle cell disease, or the presence of certain risk factors such as IV drug abuse, diabetes mellitus, or HIV infection can predispose a joint to infection. Any cause of bacteremia can seed the joint because the synovium does not have a basement membrane.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
261
USMLE Step 2 l Internal Medicine
Note
Gas gangrene is not common; a large referral center may admit 10 cases per year.
However, incidence increases during times of war.
Note
In the past, uterine gangrene was a major complication of improper abortion.
Microbiology. Nongonococcal:
Gram-positive (>85); (S. aureus [60%], Streptococcus [15%], Pneumococcus [5%])
Gram-negative (10–15%)
Polymicrobial (5%)
Presentation includes the following:
Nongonococcal: monoarticular in >85%, with a swollen, tender, erythematous joint with a decreased range of motion (knee most common); skin manifestations rare
Gonococcal: polyarticular in 50%; a tenosynovitis is much more common (effusions less common; migratory polyarthralgia common; skin manifestations with petechiae or purpura common)
Diagnosis
Nongonococcal. Culture of joint aspirate fluid is positive in 90–95% and Gram stain is positive in 40–70%. Cell count of synovial fluid is high (>50,000) and is predomi- nantly PMNs with a low glucose. Blood culture is positive in 50%.
Gonococcal. Much harder to culture. Only 50% of joint aspirates have positive synovial fluid culture; <10% of blood cultures are positive. Other sites such as cervix, pharynx, rectum, and urethra may also be positive. In the aggregate, culture of the other sites has a greater yield than culturing the joint itself.
Treatment. Bacterial arthritis is usually treated by a combination of joint aspiration and anti- microbial therapy.
Nongonococcal. In the absence of a specific organism seen on a stain or obtained from culture, good empiric coverage is nafcillin or oxacillin (or vancomycin) com- bined with an aminoglycoside or a third-generation cephalosporin. Combine an antistaphylococcal/antistreptococcal drug with a Gram-negative drug.
Gonococcal. Ceftriaxone is the drug of choice.
Gas Gangrene (Clostridial Myonecrosis)
Gas gangrene is the necrotizing destruction of muscle by gas-producing organisms, associated with signs of sepsis. It is largely caused by the spread of infection from wounds contaminated by Clostridium perfringens (the toxins produced by clostridia play a significant role in tissue damage). It is strongly associated with traumatic injury (50%), shrapnel in war, and motor vehicles in peacetime. The trauma may be as minor as an intramuscular injection; however, the wound must be deep, necrotic, and without exit to the surface. Postoperative (30%), nontraumatic (20%).
Symptoms usually begin <1–4 days of incubation after the wound; they include pain, swelling, and edema at the site of the wound. Later hypotension, tachycardia, and fever can occur.
Crepitation over the site and renal failure are late developments, usually prior to death.
Diagnosis. A Gram stain of the wound shows Gram-positive rods, but no white cells. A culture may be positive for C. perfringens as early as 1 day; however, this is not necessarily diagnostic because up to 30% of wounds can be colonized by Clostridia. Gas bubbles on x-ray are suggestive but may be caused by streptococci as well. Direct visualization (usually at surgery) of pale, dead muscle with a brownish, sweet-smelling discharge is ultimately diagnostic.
Treatment. High-dose penicillin (24 million/day) or clindamycin (if penicillin allergic) is necessary, but surgical debridement or amputation is the absolute center of treatment. Hyper- baric oxygen may be of benefit, but this is still controversial.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
262
Chapter 7 ● Infectious Diseases
Clinical Recall
What is the most appropriate treatment strategy in the management of gas gangrene?
High-dose penicillin
Clindamycin
High-dose penicillin and hyperbaric oxygen
IV doxycycline and surgical debridement
High-dose penicillin and surgical debridement
Answer: E
CARDITIS
A 40-year-old man is brought to the hospital because of fever. He has a history of IV drug use. On physical examination, there is a systolic murmur at the lower left sternal border.
Infective endocarditis is colonization of heart valves with microbial organisms causing friable infected vegetations and valve injury. Bacterial endocarditis produces large vegetations and may affect any value in the heart, although left-sided lesions of the aortic and mitral valves are more common.
There are several important invasive and other predisposing factors to bacterial endocarditis:
Prosthetic heart valves
Catheters in the right heart
Pressure-monitoring catheters
IV drug use
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
263
USMLE Step 2 l Internal Medicine
Table 7-4. Relative Risk of Predisposing Conditions for Infective Endocarditis
High Risk | Intermediate Risk | Low/Negligible Risk |
Prosthetic valves* | Mitral valve prolapse with regurgitation | Mitral prolapse without regurgitation |
Aortic valve disease | Mitral stenosis | Atrial septal defect |
Mitral regurgitation | Tricuspid valve disease | Luetic aortitis |
Patent ductus arteriosus | Hypertrophic obstructive cardiomyopathy | Transvenous pacemakers |
Arteriovenous fistula | Calcific aortic sclerosis Tetralogy of Fallot | Surgically corrected congenital lesions (no prosthesis) >6 mo after surgery |
Coarctation of the aorta In dwelling right heart catheters (hyperalimentation) | Aortocoronary bypass surgery Cardiac pacemakers | |
Previous infective endocarditis | ||
Marfan syndrome |
*Indication for endocarditis prophylaxis.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
264
Chapter 7 ● Infectious Diseases
Table 7-5. Microorganisms Responsible for Infective Endocarditis
Organism | Incidence, % |
Native valves Streptococcus viridans | 50–60 |
Enterococci | 5–15 |
Other streptococci: | 15–20 |
Staphylococcus aureus | 20–30 |
Staphylococcus epidermidis | 1–3 |
Gram-negative bacilli | <5 |
Fungi (Candida, Aspergillus, Histoplasma) | <3 |
Culture negative | |
In narcotic addicts | |
Staphylococcus aureus | |
Staphylococcus epidermidis | |
Streptococci | |
Enterococci | |
Gram-negative bacilli | |
Fungi | |
Diphtheroids | |
Prosthetic valves | |
Staphylococcus epidermidis Streptococcus viridans Staphylococcus aureus | |
Enterococci | |
Other streptococci | |
Culture negative | <5 |
Acute infective endocarditis is caused by bacteremia.
S. aureus is the most common cause of acute endocarditis
Seed previously normal valves, producing necrotizing, ulcerative, invasive infection
Produces large, bulky vegetations (2 mm to 2 cm) on the atrial side
IV drug use a major risk factor
Rapid onset with fever and sometimes sepsis
Splenomegaly
Associated with invasion of myocardium (abscess cavities) and rapid valve destruction
Embolic complications, particularly to the lungs with right-sided lesions
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
265
USMLE Step 2 l Internal Medicine
With subacute infective endocarditis, viridans group streptococci is the most common organism. It is associated with low virulence.
Seed previously abnormal valves
Produce smaller vegetations composed of fibrin, platelets, debris, and bacteria
Risk factors include ventricular septal defect with shunt; stenosis of any valve; pros- thetic valve; indwelling catheter; bicuspid aortic valve; mitral valve prolapse; and Marfan syndrome
Clinical course has slow onset with vague symptoms, leading to malaise, low-grade fever, weight loss, and flu-like symptoms. Destruction of valves is also present.
Less fatal than acute endocarditis: 5-year survival 80–90% with treatment
Clinical manifestations
Table 7-6. Incidence of Clinical Findings in Infective Endocarditis
Heart murmur or changing murmur, 80–90 | |
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
266
Chapter 7 ● Infectious Diseases
Table 7-7. Peripheral Manifestations of Infective Endocarditis
Physical Findings (Frequency) | Pathogenesis | Most Common Organisms |
Petechiae (20–30%): red, nonblanching lesions in crops on conjunctivae, buccal mucosa, palate, extremities | Vasculitis or emboli | Streptococcus, Staphylococcus |
Splinter hemorrhages (15%): linear, red-brown streaks most suggestive of IE when proximal in nailbeds | Vasculitis or emboli | Staphylococcus, Streptococcus |
Osler’s nodes (5–10%): 2–5 mm painful nodules on pads of fingers or toes | Vasculitis | Streptococcus |
Janeway lesions (10–15%): macular, red, or hemorrhagic, painless patches on palms or soles | Emboli | Staphylococcus |
Roth’s spots (<5%): oval, pale, retinal lesions surrounded by hemorrhage | Vasculitis | Streptococcus |
Complications of infective endocarditis are as follows:
Septic embolization (related to infarctions and metastatic infections): brain (“mycotic” aneurysm); spleen (greater with subacute); kidneys; coronary arteries
Glomerulonephritis with nephrotic syndrome or renal failure (immune complex)
Diagnosis. To diagnose endocarditis, 2 major criteria are required: positive blood cultures and abnormal echocardiogram.
The sensitivity of transthoracic echo is <60%, but its specificity is excellent.
Transesophageal echo is >90% sensitive and >95% specific.
If 1 of the major criteria is absent, 1 major plus 3 minor criteria will constitute a diagnosis. The minor criteria are:
Fever
IV drug use
Vascular phenomena (arterial embolic, septic pulmonary infarcts, Janeway lesions), immunologic phenomena (such as Osler nodes, Roth spots, glomerulonephritis, or a positive rheumatoid factor)
Microbiologic evidence (positive blood cultures not meeting major criteria or evidence of active infection with an organism consistent with infective endocarditis)
Treatment. Treatment decisions for infective endocarditis should be based on the identification of the organism found in blood culture and its specific antimicrobial sensitivities. Prior to the results of blood cultures, therapy can be started if the patient is very ill or there is very clear evidence of endocarditis such as fever, a clearly new or changing murmur, and embolic phe- nomena. Acceptable empiric therapy would be a combination of an antistaphylococcal drug such as nafcillin (or oxacillin), a streptococcal drug such as penicillin (or ampicillin), and gentamicin. You must alter therapy as soon as a specific microbiologic agent is known. Vanco- mycin and gentamicin are the standard empiric treatment for infective endocarditis.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
267
USMLE Step 2 l Internal Medicine
Table 7-8. Therapy of Specific Microorganisms Causing Endocarditis
Organism | Medication | Duration |
Strep. viridans | Penicillin Penicillin-allergic: ceftriaxone or vancomycin Penicillin or ceftriaxone + 2 weeks of gentamicin | 4 weeks 4 weeks 4 weeks |
Staph. aureus, native valve (Methicillin-sensitive) (Methicillin-resistant) | Nafcillin (+ 5 days of gentamicin) Penicillin-allergic: cefazolin or vancomycin + gentamicin for first 5 days Vancomycin | 4–6 weeks 4–6 weeks 4–6 weeks |
Enterococcal | Penicillin (or ampicillin) and gentamicin (vancomycin if penicillin-allergic) Penicillin-allergic or resistant: vancomycin | 4–6 weeks 4–6 weeks |
Note the criteria for surgery in infective endocarditis.
Extravalvular infection (atrioventricular block, purulent pericarditis)
Single systemic embolic event
Large aortic or mitral vegetations on echocardiography
Premature mitral valve closure in acute aortic insufficiency
Prosthetic valve infection due to organisms other than highly penicillin-sensitive streptococci
Tricuspid endocarditis due to Gram-negative bacilli
Persistent fever without other identifiable cause
New regurgitation in an aortic prosthesis
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
268
Chapter 7 ● Infectious Diseases
Gold Standard Multimedia Inc., 2007
Figure 7-10. Embolic Features of Acute Endocarditis
Figure 7-11. Petechial Hemorrhage, an Embolic Phenomenon Due to Septicemia/Endocarditis
Prevention of bacterial endocarditis
The number of cardiac lesions which are an indication for endocarditis prophylaxis has mark- edly diminished over the years. AS, MS, AR, and MR no longer need prophylaxis, even for dental procedures. Prophylactics are indicated when there is both a serious underlying cardiac defect and a procedure causing bacteremia.
Dental procedures: amoxicillin; for penicillin-allergic patients, use clindamycin, azithromycin, clarithromycin, or cephalexin
Urinary or GI procedures: no longer require prophylaxis
Cardiac Conditions Which Do Require Prophylactic Therapy
Prosthetic cardiac valves, including bioprosthetic and homograft valves
Previous bacterial endocarditis, even in the absence of heart disease
Most congenital cardiac malformations, especially cyanotic lesions (negligible risk with isolated ASD) if not repaired
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
269
USMLE Step 2 l Internal Medicine
Conditions Which Do Not Require Prophylactic Therapy
Surgically corrected systemic pulmonary shunts and conduits
Rheumatic and other acquired valvular dysfunction, even after valvular surgery
Hypertrophic cardiomyopathy
Mitral valve prolapse with valvular regurgitation
Surgically repaired intracardiac defects
Dental or Surgical Procedures Which Predispose to Endocarditis
Dental procedures known to induce gingival or mucosal bleeding, including profes- sional cleaning
Tonsillectomy and/or adenoidectomy
Surgical operations that involve intestinal or respiratory mucosa
Lyme disease is spread by the bite of the Ixodes scapularis (dammini) tick. On the basis of animal studies we know that the tick needs at least 24 hours of attachment to transmit the Borrelia burgdorferi organism. The tick is small, and the bite is often not remembered.
Symptoms begin 3–30 days after the bite of the tick.
Erythema migrans rash at the site of the bite (80% of patients)
An erythematous patch, which may enlarge in the first few days, may have partial central clearing, giving it a “bull’s-eye” appearance, although this is not commonly seen.
The rash will resolve in several weeks, even without treatment.
Flulike illness with fever, chills, and myalgias (50% of patients)
Neurologic symptoms several weeks later (10–20% of patients)
Most common symptom is paralysis of the seventh cranial nerve (facial paralysis), possibly be bilateral
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
270
Chapter 7 ● Infectious Diseases
– Meningitis, encephalitis, headache, and memory disturbance may develop as well
Cardiac symptoms (<10% of patients)
Most common symptom is AV heart block
Myocarditis, pericarditis, and various forms of arrhythmias may develop as well
Joint involvement months to years later (up to 60% of patients)
Most commonly a migratory polyarthritis, although chronic monoarticular arthritis (most commonly affecting the knee) is sometimes seen
Diagnostic criteria for (definite) Lyme are the development of the erythema migrans rash plus at least one late manifestation, as well as lab confirmation of the presence of the organ- ism. Most patients are treated on the basis of the presence of the rash alone.
Serologic testing is the most commonly used test. An ELISA test combined with a Western blot is the standard method of establishing the diagnosis. The problem with serologic testing is that it often does not distinguish between current and previous infection. Also, in early disease when patients have the rash, testing is often negative because patients have not had sufficient time to mount an immune response. In such circumstances, treatment should be given based on strong clinical suspicion, and serologic testing should not be done. Serology will almost always be positive later in the course of the disease.
Treatment. Treat minor symptoms with doxycycline or amoxicillin. Treat the rash, facial palsy, and joint pain with oral doxycycline. Treat more serious manifestations such as heart block, meningitis, myocarditis, or encephalitis with IV ceftriaxone. In other words, all cardiac and serious neurologic manifestations should be treated with IV ceftriaxone.
Centers for Disease Control and Prevention, James Gathany
Figure 7-12. Erythema-Migrans – Lyme Disease
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
271
USMLE Step 2 l Internal Medicine
Clinical Recall
Which of the following is an indication for prophylactic therapy in the management of infective endocarditis?
Congenital cyanotic heart lesions
Surgically corrected systemic pulmonary shunts
Hypertrophic cardiomyopathy
Mitral valve prolapse with valvular regurgitation
GI surgery
Answer: A
Rocky Mountain spotted fever (RMSF) is a bacterial infection caused by the organism
rickettsii is transmitted by the wood tick. The most common areas are the mid-Atlantic coast, upper South, and Midwest of the United States.
Symptoms include confusion, lethargy, dizziness, irritability, stiff neck, and GI symptoms. Rash starts by day 6.
Diagnosis is made with specific serology and a skin lesion biopsy. Treat with doxycycline.
phil.cdc.gov
Figure 7-13. Rash of Rocky Mountain Spotted Fever on an Infant
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
272
Chapter 7 ● Infectious Diseases
ACQUIRED IMMUNE DEFICIENCY SYNDROME
Acquired immune deficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV). The primary mechanism of HIV is infection of a particular subset of T lympho- cytes called CD4 cells (often called just T cells). Over time, HIV decreases the number of CD4 cells. As a person’s CD4 count drops, he becomes at increasing risk of developing opportunistic infections and certain malignancies.
The mode of HIV acquisition varies around the world.
In the United States, the earlier part of the epidemic was fueled by men who had sex with men (MSM) and injection drug use. Today, the most common risk factors are MSM and heterosexual intercourse. In women, the most common mode is heterosex- ual transmission.
In most developing countries, including Africa, Asia, and Latin America, heterosexual transmission is the primary mode.
There is often a 10-year lag between contracting HIV infection and developing
the first symptoms. That is because CD4 cells drop at a rate of 50–100/μL/year without therapy. It would take 5–10 years to drop from a normal CD4 count of 700/mm3 to a count of 200/mm3.
Opportunistic Infections in AIDS
Pneumocystis jiroveci (formerly carinii) (CD4 count <200/µL)
Principal Manifestations. pneumonia; dyspnea on exertion; dry cough; fever; chest pain; usually subacute onset and progression.
Principal Diagnostic Test. Bronchoscopy with bronchoalveolar lavage for direct identification of the organism. Chest x-ray reveals bilateral, interstitial infiltrates. Pneumothorax may be present and it is possible to have PCP pneumonia with a normal chest x-ray. Serum LDH is usually moderately elevated.
Treatment and Side Effects
Trimethoprim-sulfamethoxazole (TMP-SMZ) is the first-line therapy for mild-severe disease and may cause a rash. Alternative therapy for mild-moderate disease is a combination of dapsone and trimethoprim or primaquine and clindamycin or atovaquone or trimetrexate (with leucovorin).
Pentamidine—pancreatitis, hyperglycemia, hypoglycemia
Steroids are used as adjunctive therapy for any patient with severe pneumonia. Severe is defined with a Pao2 of <70 mm Hg or an A-a gradient of >35 mm Hg.
Prophylaxis (in Order of Preference)
TMP/SMZ orally—this is most effective.
Dapsone
Atovaquone
Aerosolized pentamidine—fails the most
Prophylaxis of PCP may be discontinued if antiretrovirals raise CD4 count >200/μL for >6 months.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
273
USMLE Step 2 l Internal Medicine
Cytomegalovirus (CD4 <50/µL)
Principal Manifestations
Retinitis: blurry vision, double vision, or any visual disturbance in a patient with a very low CD4 count
Colitis: diarrhea (<20% of patients)
Esophagitis: odynophagia, fever, retrosternal chest pain (endoscopy reveals multiple
shallow ulcers in the distal esophagus)
Encephalitis: altered mental status, cranial nerve deficits
Principal Diagnostic Tests
Funduscopy for retinitis
Colonoscopy with biopsy for diarrhea or upper GI endoscopy with biopsy of ulcers
Valganciclovir—an oral prodrug of ganciclovir, achieves levels in the serum compa- rable to IV ganciclovir. This drug can be used to treat CMV retinitis (along with intravitreal ganciclovir) and GI manifestations of CMV disease. IV ganciclovir is reserved for serious CNS infections and for patients that cannot tolerate oral medica- tions. Foscarnet and cidofovir are used when ganciclovir resistance or failure occurs.
Prophylaxis. Valganciclovir is used for maintenance therapy. Primary prophylaxis is not indicated.
Mycobacterium avium complex (CD4 <50/µL)
Principal Manifestations. A ubiquitous atypical mycobacteria found in the environment; mode of infection is inhalation or ingestion. Fevers, night sweats, bacteremia, wasting, anemia, diarrhea.
Culture of bone marrow, liver, or other body tissue or fluid
Treatment. Clarithromycin and ethambutol ± rifabutin.
Prophylaxis
Azithromycin orally once a week or clarithromycin twice a day
Prophylaxis may be discontinued if antiretrovirals raise the CD4 count >100/μL for several months.
Toxoplasmosis (CD4 <100/µL)
Principal Manifestation. Brain mass lesion: headache, confusion, seizures, and focal neuro- logic deficits
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
274
Chapter 7 ● Infectious Diseases
Principal Diagnostic Tests
CT or MRI scan of the head showing a “ring” (contrast) enhancing lesion with edema and mass effect. A trial of specific therapy is given for 2 weeks, and the scan is repeated. Shrinkage of the lesions is considered diagnostic.
Brain biopsy is occasionally necessary if there is no shrinkage of the lesions with treat- ment for toxoplasmosis.
Treatment. Pyrimethamine and sulfadiazine. Clindamycin can be substituted for sulfadiazine in the sulfa-allergic patient. Leucovorin is given to prevent bone marrow suppression.
Prophylaxis
TMP/SMZ
Dapsone
Cryptococcosis (CD4 <100/µL)
Principal Manifestation. Meningitis; patients mostly present with fever, headache, and malaise.
Principal Diagnostic Tests
Lumbar puncture with initial evaluation by India ink and then specific cryptococcal antigen testing. A lower CSF cell count implies worse disease.
Serum cryptococcal antigen testing. A high antigen titer, high opening pressure, and low CSF cell count all imply a worse prognosis.
Treatment. Amphotericin intravenously for 10–14 days at least (with flucytosine), followed by fluconazole orally for maintenance and suppressive therapy.
Prophylaxis. Oral fluconazole is not recommended for general use as a prophylaxis. This is because the incidence of cryptococcal meningitis is too low to demonstrate a mortality benefit with its use.
Vaccinations
All HIV-positive persons should receive vaccinations for pneumococcus, influenza, and hepatitis B. If the CD4 level is >200, even varicella vaccine can be given.
Monitoring the Immune System
CD4 count monitoring and viral load testing can be compared to the staging of cancer in terms of assessing prognosis for the patient. They are indispensable for determining appropri- ate treatment.
CD4 cell count
The CD4 count is the most accurate method for determining what infections or other diseases the patient is at risk for. At the present time the CD4 count provides an assessment of the extent of immunologic damage at the time of diagnosis and is usually the most important factor when deciding the timing of therapy. It is also the strongest predictor of disease progres- sion and survival. Without treatment, CD4 count drops 50–100 cells per year.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
275
USMLE Step 2 l Internal Medicine
The following is an approximate breakdown of when the risk of certain diseases begins to increase.
CD4 Count 700–1,500/μL: Normal
200–500/μL: Oral thrush, Kaposi sarcoma, tuberculosis, Zoster
100–200/μL: Pneumocystis carinii pneumonia, disseminated histoplasmosis and coccidiomycosis
<100/μL: Toxoplasmosis, Cryptococcus, cryptosporidiosis, disseminated herpes simplex
<50/μL: Cytomegalovirus, Mycobacterium avium complex. Progressive, multifocal leukoencephalopathy (PML), CNS lymphoma
In addition to determining the risk of opportunistic infections, the other uses of the CD4 count are to determine:
Adequacy of response to antiretroviral medications (though the best test to monitor response to therapy is the HIV-RNA viral load)
Tests now exist to give a numerical value to the quantity of HIV in the blood. Viral load can be compared to glucose level for patients with diabetes. Monitoring of viral load is the best method to monitor adequate response to therapy when the patient is on antiretroviral medica- tions and the goal is undetectable viremia. High viral loads indicate a greater risk of complica- tions of the disease and a worse prognosis. A high viral load generally indicates that the level of CD4 cells is going to drop more rapidly.
The adequacy of response to antiretroviral medications; usually with current assays, the goal is complete suppression of viremia with <50 to 70 copies of HIV-RNA/mL
Viral sensitivity/resistance monitoring
Viral sensitivity testing is done to determine which antiviral medications will be effective in an individual patient. Sensitivity testing should always be done if a patient is failing a combination of medications and a change in therapy is necessary. It should also be done in any pregnant woman who has not been fully suppressed on the initial combination of medications.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
276
Chapter 7 ● Infectious Diseases
Antiretroviral Therapy
Currently available agents and their major adverse effects
Nucleoside Reverse Transcriptase Inhibitors
Zidovudine (ZDV or AZT): leukopenia, anemia, GI
Didanosine (DDI): pancreatitis, peripheral neuropathy
Stavudine (D4T): peripheral neuropathy
Lamivudine (3TC): nothing additional to placebo
Emtricitabine: structurally related to lamivudine; few side effects as for lamivudine
Tenofovir: a nucleotide analog as compared to the others that are nucleoside analogs
Abacavir: most important side effect is a hypersensitivity reaction usually seen in first 6 weeks; may involve a rash, fever, nausea/vomiting, muscle and joint aches, and shortness of breath
– If hypersensitivity reaction occurs, stop drug immediately and do not restart; recurrence of hyperactivity symptoms can be rapid and life-threatening
Zalcitabine (DDC): pancreatitis, peripheral neuropathy, lactic acidosis
Protease Inhibitors. Hyperlipidemia, hyperglycemia, and elevated liver enzymes for all in the group; abnormal fat loss (lipoatrophy) from the face and extremities with redistribution of fat in the back of the neck and abdominal viscera can be seen.
Amprenavir
Atazanavir: diarrhea, asymptomatic hyperbilirubinemia
Non-Nucleoside Reverse Transcriptase Inhibitors. These drugs are noncompetitive inhibitors of reverse transcriptase.
Efavirenz—Neurologic; somnolence, confusion
Nevirapine—Rash, hepatotoxicity
Delavirdine—Rash
Rilpivirine
Guidelines for starting therapy
Start therapy once HIV is diagnosed, regardless of CD4 count. Regarding what to start:
Use 2 nucleosides combined with a protease inhibitor or
Use 2 nucleosides combined with efavirenz
Emtricitabine, tenofovir, and efavirenz are available as a single pill once a day.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
277
USMLE Step 2 l Internal Medicine
Note
Efavirenz is the only antiretroviral medication that is contraindicated in pregnancy.
A combination therapy (highly active antiretroviral therapy, HAART) should be used with medications having synergistic activity by acting at different sites of the virus replicative process; hence current guidelines recommend two NRTIs (usually tenofovir/emtricitabine or zidovudine/lamivudine) combined with either an NNRTI (efavirenz preferred) or a PI (atazanavir/ritonavir, fosamprenavir/ritonavir, or lopinavir/ritonavir).
Giving “boosted protease inhibitors” is the practice of giving most protease inhibitors in combination with a low dose of ritonavir (also a PI). Ritonavir given alone as a PI has modest efficacy and significant drug interactions, but when given in a low dose with other PIs, it decreases their metabolism and enables higher drugs levels of the “boosted” PI over a pro- longed period of time. This increases chances of success and also decreases pill burden.
Any regimen that increases the CD4 count and drops the viral load to undetectable amounts or close to undetectable amounts is considered adequate therapy. When starting medication, a drop of at least 50% of viral load in the first month is expected to indicate adequate therapy.
Without treatment, approximately 25–30% of children born to HIV-positive mothers will truly be HIV positive. All children at birth will carry the maternal antibody to the virus and will be positive by ELISA testing, but only 25–30% will remain truly infected.
Pregnant women with serious disease (i.e., low CD4 or high viral load) should be treated fully for their HIV infection. That is, they should get triple antiretroviral therapy as you would in a nonpregnant person.
C-section is only used routinely in those whose CD4 count and viral load are not controlled with medications (when viral load is >1000 copies/mL of HIV-RNA at the time of delivery).
Treatment is indicated in all pregnant women. Zidovudine (AZT) should be used in combination with 2 other antiretroviral medications. Even when the CD4 is high and viral load is <1000, you should start therapy as soon as you know the patient is pregnant.
Breast feeding is associated with transmission of virus to the infant. If a pregnant woman is already on antiretrovirals, she should continue on them. She should start immediately regard- less of gestational age. If the woman has high CD4 cells and does not need treatment for herself, combination therapy can end after delivery. The majority of women can deliver with a normal vaginal delivery. Avoid efavirenz in pregnancy.
Postexposure Prophylaxis (e.g., Needlestick Injury)
All persons with serious exposure to blood containing body fluids of HIV-positive patients should receive AZT, lamivudine, and nelfinavir or raltegravir or any other fully suppressive 3-drug combination for 4 weeks. Modify the regimen as needed to ensure compliance. The point is to use any fully suppressive combination for at least 4 weeks; we know zidovudine alone will decrease the risk of transmission by 80%. We don’t know how much the combina- tion will decrease transmission.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
278
Chapter 7 ● Infectious Diseases
Tetanus
Tetanus is a severe infectious complication of wounds caused by the toxin of Clostridium tetani
(neurotoxin); takes 1–7 days to develop; spore forming, Gram-positive rod.
Clinical Findings. Tonic spasms of voluntary muscles; respiratory arrest; difficulty in swallowing (dysphagia); restlessness; irritability; stiff neck, arms, and legs; headache; lockjaw; flexion of the arms and extension of the lower extremities; and high mortality rate. Diagnosis is clinical.
Treatment is prophylactic:
Tetanus toxoid (Tdap) boosters every 10 years
Immediate surgical care, débride wound
Antitoxin, tetanus immunoglobulin
Penicillin 10–14 days
Patient | ||
Linear, 1 cm deep cut, without devitalized tissue, without major contaminants, | Blunt/missile, burn, frostbite, 1 cm deep; devitalized tissue present | |
Not completed primary or vaccination history unknown | ||
Completed primary series | ||
*TIG = tetanus immunoglobulin (human)
Aspergillosis
Aspergillosis is a fungus that is widespread in the environment; it primarily causes pulmonary disease in the immunocompromised.
Etiology
90% species known, with A. fumigatus the most common
Ubiquitous in natural decaying organic matter, ceiling tile, and ventilation systems
Spores can be isolated from air anywhere on earth
Signs and Symptoms
Various degrees of respiratory tract invasion
Rarely it can disseminate to any organ but starts in the lung
Allergic bronchopulmonary-like asthma with cough/fever/wheezing
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
279
USMLE Step 2 l Internal Medicine
Note
Voriconazole and caspofungin are used to treat aspergillosis and some other fungal infections.
Mycetoma—literally a “fungal ball”: 1) Sets up residence in a pre-existing cavity, with hemoptysis as chief complaint; and 2) it is not invasive.
Invasive pulmonary
90% have 2 of these 3 risks: 1) neutropenia <500, 2) steroid use, and 3) cytotoxic drugs (e.g., azathioprine, cyclophosphamide).
Diagnosis. Depends on the type of disease being caused; however, all can have an abnormal chest x-ray and Aspergillus in sputum.
Allergic bronchopulmonary elevation of markers of allergy/asthma, such as eosino- phil/IgE levels
Positive skin testing
Mycetoma: abnormal sputum culture/serum precipitins/x-ray
.Treatment. Depends on syndrome (really, they are separate diseases).
Allergic: steroid taper and asthma medications, not antifungals
Invasive: Voriconazole is superior to amphotericin; there are fewer failures seen with it (and caspofungin) as compared with amphotericin. Itraconazole for very mild disease or after initial treatment with amphotericin. Caspofungin is active against Aspergillus and may be superior to amphotericin. Caspofungin is an echinocandin. The other echino- candins are micafungin and anidulafungin. Echinocandins have virtually no toxicity.
Which of the following statements regarding HIV in pregnant women is correct?
Emtricitabine is contraindicated in pregnant women
C-sections are done when the viral load is >1000 copies/mL of HIV-RNA at the time of delivery
Treatment with HAART triple therapy is done only in women who are at high risk of transmitting the disease
Only give HAART triple therapy to pregnant patients with opportunistic infections
Answer: C
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
280
ChNaepherroTloitglye #8
Learning Objectives
Outline the approach to investigating kidney problems, fluid and electrolyte disorders, and acid-base disturbances
Describe the presentation, diagnosis, and management of acute renal failure, renal tubular acidosis, glomerulonephritis, nephrolithiasis, hereditary cystic disease, and end-stage renal disease
List the indication and complications of dialysis and criteria to qualify for renal transplantation
Describe the renal causes of hypertension and their management
ACUTE RENAL FAILURE
Acute renal failure (ARF), or better referred to as acute kidney injury (AKI), is a rapid rise in blood urea nitrogen (BUN) and creatinine over several hours to days. There is no precise dura- tion to define it as acute.
In rhabdomyolysis or contrast-induced renal failure, it may develop over several hours.
In aminoglycoside toxicity or poststreptococcal glomerulonephritis, it may develop in several weeks.
There are several terms for renal failure, which all roughly mean a rise in creatinine and a
decrease in renal function or glomerular filtration rate.
Renal insufficiency means renal failure, but not to the point of needing dialysis (the term azotemia can be used interchangeably; literally, it means the buildup of azole groups or nitrogen in the blood).
Uremia (which means urea in the blood) describes very severe renal failure in which dialysis is needed to save life (the term end-stage renal disease can be used interchange- ably). The renal dysfunction is life-threatening. Clinical presentation includes:
Severe acidosis, mental status changes, hyperkalemia, and fluid overload
Anemia, hypocalcemia, and possible pericarditis
Bleeding diathesis due to platelet dysfunction
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
281
USMLE Step 2 l Internal Medicine
Uremia does not necessarily mean the same thing as chronic renal failure. Although most patients develop uremia after years of renal insufficiency such as from diabetes or hypertension, it is possible to become uremic in as little as 1–2 weeks with a severe illness such as tumor lysis syndrome or rhabdomyolysis.
AKI is also classified as prerenal, postrenal, or intrarenal to determine the site of the defect.
Prerenal azotemia means decreased perfusion of the kidney.
Postrenal azotemia means decreased drainage from the kidney or decreased forward flow of urine. In both prerenal and postrenal azotemia, the kidney is not intrinsically defective. If the kidney in prerenal or postrenal azotemia were taken out and transplanted into another person, it would function normally.
Intrarenal means there is a tubular or glomerular problem, and the kidney itself is defective.
Diagnostic Tests. In any form of renal failure, the BUN becomes abnormally elevated. It can also be falsely elevated even when renal function is normal, in response to increased protein load in the diet or GI bleed. This is also from increased catabolism. The BUN is derived from protein waste products; blood in the gut acts like a big protein meal.
The BUN will improve after a session of dialysis. The BUN can be falsely low when there is liver disease, malnutrition, or SIADH. The BUN level corresponds to the degree of renal failure; the higher the BUN, the worse the kidney function.
Creatinine, a metabolic product of skeletal muscle, is our main measure of renal function. Creatinine clearance is our closest approximation of glomerular filtration rate (GFR) without the use of more cumbersome testing such as clearance of inulin. Inulin does not naturally exist in the human body.
Creatinine clearance slightly overestimates GFR because there is some tubular secretion of creatinine.
Creatinine can be falsely low just because of decreased muscle mass (explaining why creatinine clearance is always adjusted for weight). More muscle means more creati- nine. A bodybuilding weight lifter with 100 kg of muscle will naturally have a higher creatinine than an inactive librarian who weighs 50 kg. The higher creatinine in the bodybuilder does not necessarily mean worse renal function.
Creatinine needs some time to rise. Even if the patient becomes anuric, the creatinine will rise only at a rate of 0.5–1.0 point per day. This rise will be faster if the body muscle mass is greater. Hence, if the creatinine goes from 1 to 3 over 2 days in a patient with renal injury, this is consistent with nonfunctioning kidneys.
Prerenal Azotemia
Prerenal azotemia is a form of renal insufficiency caused by diminished perfusion of the kidney on any basis. The kidney itself is normal. If the kidney could receive adequate perfu- sion, the BUN and creatinine would normalize. The causes of prerenal azotemia include hypovolemia on any basis (dehydration, burns, poor oral intake, diuretic, vomiting, diarrhea, sweating, hemorrhage), hypotension on any basis (septic shock, cardiogenic shock, anaphylac- tic shock), and third spacing of fluids such as peritonitis, osmotic diuresis, or low aldosterone states such as Addison disease. Addison disease results in intravascular volume depletion, leading to diminished tissue perfusion.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
282
Chapter 8 ● Nephrology
Diminished perfusion from a decrease in cardiac output also results in prerenal azotemia. Although there may be total body fluid overload with significant edema, all that matters in terms of renal function is how much fluid is still in the vascular space and how much can provide meaningful perfusion of the kidney. With severe CHF, constrictive pericarditis, or coarctation of the aorta, there may be edema and fluid overload, but the kidney is receiving virtually no perfusion, hence the rising BUN and creatinine. This is the concept of effective arterial volume.
The first clue to the diagnosis of prerenal azotemia is a BUN:creatinine ratio of 20:1. There is also a low urine sodium and low fractional excretion of sodium (FeNa <1%) because the kidney perceives the body as being volume-depleted (hence, there will be a vigorous sodium and water reabsorption by the kidney). This results in a very high urine osmolality as well, because the kidney attempts to retain all the water it can in the kidney, and therefore excretes very concen- trated urine. Concentrated urine has a high specific gravity (>1.010) and high urine osmolality (>500). These lab findings are irrespective of the etiology of the prerenal azotemia. In other words, the BUN:creatinine ratio rises to 20:1, urine sodium is low, and the urine osmolality is high no matter what the etiology of the decreased perfusion or hypotension.
Low albumin states also lead to decreased renal perfusion. Nephrotic syndrome and other malabsorptive states lead to a low albumin level. This leads to renal failure.
Renal artery stenosis
Renal artery stenosis, especially if bilateral, results in high BUN and creatinine with a high BUN:creatinine ratio. Although systemic BP may be markedly elevated, the result is still a form of prerenal azotemia. There is markedly diminished renal perfusion because of the obstruction in the renal artery. The systemic BP does not matter; all that matters is how much is getting to the kidney. Hence, to the kidney, renal artery stenosis functions like hypotension. This effect is greatly exaggerated with the use of ACE inhibitors, which markedly diminish renal perfusion. This is because of the extremely high aldosterone state in renal artery stenosis.
Hepatorenal syndrome
Hepatorenal syndrome is renal failure based entirely on the presence of hepatic failure. The kidneys are normal. The rise in BUN and creatinine is believed to be due to an intense vaso- constriction of the afferent arteriole, causing decreased renal perfusion.
Because the defect is at the afferent arteriole, lab numbers are consistent with prerenal azotemia, i.e., high BUN:creatinine ratio >20:1.
Urine sodium is low (<10) and fractional excretion of sodium <1% (measure urine sodium with the patient off diuretics).
Intrinsic renal disease should be excluded to make a diagnosis.
No improvement in renal failure after 1.5 L of colloid, like albumin, is diagnostic of hepatorenal syndrome.
Treatment is correction of the underlying liver disease. Midodrine, an alpha agonist, and octreotide may be beneficial, but the best treatment is liver transplantation.
ACE inhibitor effect on the kidney
ACE inhibitor–induced renal failure is caused by vasodilation of the efferent arteriole. Angiotensin has a significant vasoconstrictive effect on the efferent arteriole; ACE inhibitors block this, causing
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
283
USMLE Step 2 l Internal Medicine
a decreased GFR that is usually transient. However, in the elderly, diabetics, hypertensives, or patients with baseline renal disease such as from myeloma, an ACE inhibitor can produce quite a marked decrease in renal function. Hence, if there is underlying renal insufficiency, there can be a rise in BUN and creatinine after initiating an ACE inhibitor. In patients with bilateral renal artery stenosis, observe for severe decline in renal function after an ACE inhibitor has been initiated.
Despite the ability of ACE inhibitors to potentially worsen renal function, their overall effect on the kidney is to diminish the rate of progression to uremia and renal failure. This beneficial effect is most likely secondary to the decrease in intraglomerular hypertension. ACE inhibitors and angiotensin receptor blockers decrease hypertension inside the glomerulus. ACE inhibi- tors decrease proteinuria by 35–45%. ACE inhibitors produce a brief decrease in GFR in the short-term, with a long-term beneficial effect on decreasing proteinuria and the rate of progression of renal failure. This is particularly true in patients with diabetes.
Postrenal azotemia is caused by any decrease in the outflow of urine. The precise etiology of the obstruction is not particularly relevant when it comes to the degree of renal failure. All that matters is that there is an obstruction bilaterally to the flow of urine out of the kidney.
One cannot get renal failure by the obstruction of a single kidney if a patient has both kidneys in place, i.e., a large stone in one ureter cannot cause renal failure because creatinine does not rise if there is loss of only one kidney.
A small stone or clot in the bladder can obstruct both kidneys, and this can cause postrenal azotemia. Other causes of postrenal azotemia include bladder cancer, prostate hypertrophy/cancer, bilateral ureteral disease e.g., retroperitoneal fibrosis, neurogenic bladder, or any other cause of bilateral obstructive disease. Strictures can cause this problem but only if they are bilateral in location.
The complete obstruction of a single kidney does not cause renal failure because only 35% of one kidney is needed in order to live. Creatinine will begin to rise only 70–80% of renal function has been lost. Thus, more renal function is lost as one goes from creatinine 1 to 2 than from creatinine 2 to 10. Patients usually have a preceding history of obstructive symptoms followed by sudden onset of oliguria or anuria. Neurologic causes such as MS, spinal cord lesion, and neuropathy may lead to poor function of the urinary bladder and obstruction.
Initially, BUN and creatinine will elevate in a ratio 20:1 as it does with prerenal azotemia. There will also be a low fractional excretion of sodium (FeNa) and low urine sodium. When the obstruction continues for such a long time that there is permanent damage to the kidney and the kidney tubule cells die, then the BUN:creatinine ratio will lower to 10:1, as is seen in acute tubular necrosis (ATN). Early diagnosis is, therefore, essential. Complete recovery is pos- sible until 10–14 days of obstruction.
ATN is the most common cause of AKI (intrinsic) in hospitalized patients.
The diagnosis of postrenal azotemia is determined by finding a distended bladder on examina- tion, bilateral hydronephrosis on renal sonogram or CT scan, or by finding large volumes of urine in the bladder after passing a Foley urinary catheter. After urinating (voiding), there should be no more than 50 mL of urine left in the bladder. If this post-void residual is mark- edly elevated, it implies an obstruction to the flow of urine out of the bladder.
Treatment is based on relieving the cause of the obstruction.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
284
Chapter 8 ● Nephrology
Intrarenal: Tubulointerstitial Disease
Acute tubular necrosis
Acute tubular necrosis (ATN) is acute renal failure on the basis of tubular damage (as opposed to glomerular damage), or simply decreased perfusion of the kidney or drainage out of the kid- ney. About 85% of acute renal failure is secondary to intrinsic renal disease such as ATN.
ATN is caused by hypoperfusion of the kidney, leading to such severe ischemia that there is cellular death or by a toxic injury to the kidney such as aminoglycoside toxicity or from amphotericin (caused by sepsis or post-cardiac/aortic surgery).
ATN often occurs from a combination of toxic and ischemic injury. If tissue ischemia seems similar in concept to what was described for prerenal azotemia, that is because there is overlap. It is like the difference between myocardial ischemia and a myocar- dial infarction.
If there is modest hypotension or hypovolemia, BUN and creatinine will rise in a 20:1 ratio consistent with prerenal azotemia. Prerenal azotemia is essentially reversible.
If the ischemia becomes more severe, the tubular cells will necrose and slough off into the urine and become visible as granular, muddy brown, or pigmented casts.
At the point of necrosis, the renal insufficiency can be permanent. In less severe disease and nonoliguric ATN, urinalysis may be relatively normal.
The hypotension causing tubular ischemia can be of any etiology, i.e., surgical or medical. The degree, and especially the duration of hypotension, are extremely important. The longer the duration of hypotension/hypoperfusion, the greater the chance of ATN. The risk of ATN goes up even further when there is an added toxic injury. In other words, the likelihood of rhabdo- myolysis causing renal failure is markedly increased when there is hypoperfusion of the kidney. The same can be said of cisplatin toxicity, tumor lysis syndrome, or injury from hemoglobin toxicity.
There are 3 phases in ATN, although not everyone experiences all phases.
Prodromal: time between the acute injury and onset of renal failure
Oliguric (<400 mL/24 hrs) or anuric (<100 mL/24 hrs)
Postoliguric: diuretic phase when all the water not previously excreted will leave the body in a vigorous polyuria
Diagnosis. The initial clue is a BUN:creatinine ratio close to 10:1; by itself this ratio simply implies the damage is intrarenal (inside the kidney itself), as opposed to abnormalities of perfusion (prerenal) or drainage (postrenal). Further clues to the diagnosis of ATN are high urine sodium (>40), high fractional excretion of sodium (>1%), and low urine osmolality (<350). This is because tubular cells are responsible for forming either concentrated or dilute urine. If the tubular cells die from ischemia, then the kidney can neither concentrate nor dilute the urine. Dead cells don’t work.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
285
USMLE Step 2 l Internal Medicine
Note
Other Meds
NSAIDS
Allopurinol
Proton pump inhibitor
Note
Any sulfa drug can cause an allergic reaction. Besides antibiotics, other examples of sulfa drugs are diuretics such as thiazides, furosemide, and acetazolamide.
Table 8-1. Diagnosis: How to Confirm the Difference between Prerenal and ATN (Based on Lab Values)
Prerenal | ATN | |
Urine osmolarity | >500 | <350 |
Urine Na+ | <20 | >40 |
FeNa+ | <1% | >1% |
Urine sediment | Scant | Full (brownish pigmented granular casts, epithelial casts may be seen) |
Note: In ATN, the urine cannot concentrate. In prerenal, you hold on to all free H2O and Na+.
Treatment. Treatment focuses on correcting the underlying cause. There is no therapy that can reverse the renal failure. Hydration is often given to make sure there is no prerenal component; hydration can prevent contrast-induced renal failure, but it does not reverse it once it occurs, nor can diuretics.
ATN is a combined ischemic/toxic disease. It is like a ‘sunburn for the kidney.’ Once it occurs, all you can do is support the patient and wait to see if the renal tubular cells can restore themselves. No medical therapy reverses ATN.
If the degree of renal failure is severe and life threatening, then dialysis is used.
Allergic interstitial nephritis
Allergic interstitial nephritis (AIN) accounts for 10–15% of intrinsic renal failure. It can be distinguished from other causes of renal failure by the presence of fever and rash on physical examination and many WBCs, occasionally eosinophils.
The etiology of AIN is usually an adverse immunologic effect to medication (70% of cases). The medications most likely to be allergenic in general are those medications most likely to cause AIN. For example, skin rash from an allergic drug reaction can be caused by penicillin, cephalosporin, sulfa drugs, allopurinol, rifampin, and quinolones. These are the same medica- tions to cause AIN. In addition, many of these same drugs cause drug-induced hemolysis as well. In other words, 10% of the population is allergic to penicillins or sulfa drugs. This allergic reaction can take the form of a rash, Stevens-Johnson syndrome, hemolysis, or AIN. In the same way, calcium channel blockers rarely cause a rash. Calcium blockers also rarely cause nephritis or hemolysis.
AIN is also caused by infections themselves, such as viruses, bacteria, and fungi. The most common infections to result in AIN are leptospirosis, legionella, CMV, rickettsia, and strepto- cocci. The least common causes of AIN are several autoimmune disorders such as systemic lupus erythematosus (SLE), Sjögren syndrome, sarcoidosis, and cryoglobulins. Cryoglobulins can cause renal failure from membranous glomerulonephritis as well. Eight percent of cases are idiopathic.
Fever is present in 80% of those with AIN. It can be very difficult to determine if the fever is from the underlying illness or from the AIN. Rash is present in 25–50% of patients. Joint pain is common because AIN acts somewhat like serum sickness.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
286
Chapter 8 ● Nephrology
Lab abnormalities may include the following:
Eosinophilia, eosinophiluria, hematuria, proteinuria, increased serum IgE
Hematuria (95% of patients), though this finding is rather nonspecific. More people with AIN have eosinophils in the urine rather than in the blood.
Mild proteinuria, nearly always <2 grams/24 hrs
The best initial test for AIN is a urinalysis (UA) looking for white cells. Remember that the UA cannot distinguish eosinophils from other white cells. The most accurate test for urine eosinophils is Hansel or Wright stain of the urine. (The most accurate test for AIN is actually kidney biopsy, although that is not needed in the presence of the other findings above).
NSAID-induced injury typically lacks fever, rash, and eosinophilia.
Treatment. There is no specific therapy necessary for AIN in most patients; it should resolve spontaneously after stopping the offending agent. If renal failure persists or worsens, consider a short course of steroids.
Pigments (hemoglobin/myoglobin)
Rhabdomyolysis is caused by sudden, severe crush injury; seizures; severe exertion; and some- times by hypokalemia, hypophosphatemia, or medications such as statins. Massive hemoglobin- uria severe enough to cause renal failure is generally only caused by an ABO incompatibility.
Both of these disorders result in enough pigment release in the bloodstream to cause nephrotox- icity. The toxicity is because the pigment is directly toxic to the tubular cells as well as from precipitation of the pigment in the tubules. The degree of toxicity is related to the duration of contact of the tubular cells with the hemoglobin or myoglobin. This toxicity is compounded by dehydration. Hence, a person who has run a marathon has both myoglobin release as well as poor kidney perfusion. This is cumulative in the risk of renal failure.
The most important test with a severe crush injury or seizure and potentially life-threatening rhabdomyolysis is an EKG or potassium level. This implies that you know how a patient with rhabdomyolysis will die. Acidosis and hyperkalemia can lead to an arrhythmia. If there are peaked T-waves on the EKG, give calcium chloride or gluconate. The best initial test for rhabdo- myolysis is a UA, in which you find a dipstick positive for blood but with no red cells visible (that is because myoglobin can react with the reagent on the dipstick and come out as if there were red cells present). Hemoglobin will do the same thing. The dipstick of the UA cannot distinguish among hemoglobin, myoglobin, and RBCs. This is because myoglobin has heme in it.
Rhabdomyolysis is confirmed with the following:
Markedly elevated serum CPK level (a biochemical marker of skeletal muscle neuro- sis); for nephrotoxicity to occur, level must be in 10,000–100,000 range (normal ≤500)
Metabolic acidosis with decreased serum bicarbonate, hyperphosphatemia secondary to muscle breakdown, and hypocalcemia secondary to the deposition of calcium in damaged muscles
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
287
USMLE Step 2 l Internal Medicine
Possible severe hyperuricemia due to release of purines from damaged muscles
Very rapidly rising creatinine level due to the renal failure and massive release of muscle products; thus, BUN:creatinine ratio may be low (below 10:1)
Treatment. In general, therapy is hydration and mannitol used as a diuretic to decrease the duration of contact between the nephrotoxic hemoglobin/myoglobin and the kidney tubule. Alkalinizing the urine with bicarbonate may help prevent the precipitation of the pigment in the tubule. If there are EKG abnormalities from the hyperkalemia, the best initial therapy is calcium chloride or gluconate.
Proteins
Bence-Jones proteins, such as in myeloma, also cause tubular damage. Myeloma is most prominently a cause of nephritic syndrome, however, not tubular damage.
Oxalate. The most common cause of hyperoxaluria resulting in acute renal failure is ethylene glycol overdose in a suicidal person who ingests antifreeze. Look for an intoxicated person with metabolic acidosis and elevated anion gap who is found to have renal insufficiency. Diagnosis is confirmed with oxalate crystals seen on urinalysis (oxalate crystals are shaped like envelopes).
Treat acute ethylene glycol overdose with fomepizole infusion to prevent the formation of the toxic metabolite of ethylene glycol, which is oxalic acid. Fomepizole is preferred. It is the oxalic acid that causes the renal failure. Dialysis must also be used to then remove the ethylene glycol. Sodium bicarbonate can be given to correct acidosis.
Chronic hyperoxaluria and kidney stones can be caused by Crohn’s disease because of fat and calcium malabsorption.
Urate. Acute renal failure from uric acid toxicity occurs in the setting of tumor lysis syndrome. This is why patients with leukemia or lymphoma receive vigorous hydration and allopurinol prior to receiving chemotherapy. Allopurinol reduces the production of uric acid by inhibiting conversion of xanthine to hypoxanthine to uric acid. Uric acid stones precipitate in an acidic urine, unlike oxalate crystals, which precipitate in alkaline urine. Allopurinol treatment with alkalinization of urine markedly reduces the risk of uric acid nephropathy. Chronically, gout causes renal impairment through a slower and milder version of the same mechanism.
Hypercalcemia
In hypercalcemia, calcium precipitates in the kidney tubule, forming stones. Distal RTA and nephrogenic diabetes insipidus can also develop.
The most common cause of hypercalcemia is primary hyperparathyroidism. If there is no renal damage (or decreased GFR) and no symptoms, i.e., mild hyperparathyroidism. treatment is not surgical. If the hyperparathyroidism is associated with evidence of renal impairment, treatment is surgical resection of the glands.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
288
Chapter 8 ● Nephrology
Toxins
The most common toxins to be associated with renal insufficiency and ATN are NSAIDs; aminoglycosides; cephalosporins; contrast agents; amphotericin; chemotherapy e.g., cisplatin; radiation effect; heavy metals e.g., lead, mercury, gold; and cyclosporine. Allergic interstitial nephritis differs from direct-acting toxins in several ways:
Allergic interstitial nephritis occurs with the first dose, and is associated with fever, rash, joint pain, and eosinophils in both blood and urine.
Direct-acting toxins can take days to weeks to produce enough cumulative toxicity to cause renal failure; they are not associated with eosinophils, fever, joint pains, or rash.
There is no test which can confirm a specific toxin as the etiology of the renal failure. Other causes of renal failure must first be excluded, and the toxin must be found in the history.
Regarding treatment, there is no specific therapy that can reverse the renal insufficiency of any direct-acting toxin.
Aminoglycosides. Tobramycin is the least nephrotoxic compared with gentamicin and amikacin. Aminoglycoside toxicity generally takes 5–10 days of administration to result in toxicity. The likelihood of toxicity is associated with trough levels. Renal failure due to aminoglycosides is frequently non-oliguric (K+ levels not elevated). Hypokalemia and hypomagnesemia predispose the patient to aminoglycoside toxicity. The ability of antibiotics to kill bacteria is associated with the peak level, but the likelihood of toxicity is associated with the trough level. This is most likely because a low trough allows time for the renal tubular cells and neural cells of the inner ear to regenerate themselves. Aminoglycosides also exert a bactericidal effect after their level has become low because they enter the bacteria and continue to kill. This ability to exert an effect despite low or absent levels is called postantibiotic effect. Hence, aminoglycosides should be given once a day. Once-a-day dosing allows high bactericidal levels with the same efficacy and very low trough levels. The low trough levels reduce toxicity. Aminoglycoside-related nephrotoxicity is estimated to be between 10–20% of all drug-induced nephrotoxicity and is usually reversible.
Amphotericin B. This medication is associated with renal insufficiency as well as distal renal tubular acidosis. It is expected that after several days or weeks of amphotericin use, the patient will develop a high creatinine as well as a decreased magnesium, bicarbonate, and potassium level. These often revert to normal after the medication is stopped. This form of toxicity is from cumulative dosing.
Atheroembolic Disease. Look for a patient who undergoes a vascular catheter procedure such as angioplasty who develops renal failure several days later. Atheroemboli are also associated with eosinophilia, low complement levels, bluish discoloration of the fingers and toes, and livedo reticularis. Although the most accurate test is a skin biopsy to see choles- terol crystals in the skin, this is rarely done. There is no therapy for atheroemboli. High doses of statins have been tried.
Contrast Agents. Radiocontrast material for CT scanning can result in renal failure in as little as 12–24 hours after the use of the agent. This is one of the main ways to distinguish this form of renal failure from aminoglycoside or amphotericin toxicity, which need several days to weeks of cumulative exposure. The rise in creatinine peaks at 3–5 days after the injury. The BUN and creatinine may be up in a 20:1 ratio, such as in prerenal azotemia, because the hypertonicity of the agent provokes an intense vasospasm of the afferent arteriole. The worse the underlying renal parenchyma, the more likely the patient is to have renal failure secondary to contrast material. If you are elderly, diabetic, and hypertensive with myeloma, you are far more likely to experience contrast-induced renal insufficiency.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
289
USMLE Step 2 l Internal Medicine
Other Toxins. Pentamidine is associated with renal failure in addition to its toxicity on the pancreas. Vancomycin, cyclosporine, and lithium can all cause renal failure in a dose-depen- dent fashion. Indinavir is a protease inhibitor that results in renal failure usually from the drug precipitating out in the kidney tubules. Indinavir stones need contrast to be identified on a spiral CT scan.
Analgesic nephropathy
NSAIDs are a frequent cause of renal failure. NSAIDS cause renal failure by several mechanisms:
Interstitial nephritis
Direct toxic effect on the tubules
Papillary necrosis
Inhibition of vasodilatory prostaglandins in the afferent arteriole
A person without underlying renal insufficiency should not experience a rise in creatinine from the use of NSAIDs. That only occurs in those with significant impairment such as the elderly or those with hypertension or diabetes. NSAIDs can also cause toxicity by a combina- tion of these. More than 50% of patients have pyuria, which, if persistently associated with sterile urine, can be an important clue to diagnosis. There is no specific test to confirm that NSAIDs caused the renal failure. There will be a rise in BUN and creatinine and a history of NSAID use. There is no specific therapy other than to stop the NSAID.
Acute papillary necrosis occurs in patients with a history of sickle cell disease, diabetes, urinary obstruction, or chronic pyelonephritis. It can be brought on acutely by the ingestion of NSAIDs. The presentation is the sudden onset of flank pain, hematuria, pyuria, and fever. This can be very similar in presentation to acute pyelonephritis. In a patient with the risks described, symptoms for papillary necrosis will come on very suddenly. The findings of white and red cells on urinalysis will not distinguish them. However, papillary necrosis will not grow any organ- isms on culture. The most accurate diagnostic test for papillary necrosis is CT scan, which will show “bumpy” contours in the renal pelvis where the papillae have sloughed off. There is no specific therapy for papillary necrosis.
Prevention of contrast-induced renal failure
In patients with significant underlying renal disease who require a radiologic procedure requiring contrast, hydration with 1–2 liters of normal saline over 12 hours is required before the procedure.
Hydration has been shown to decrease the likelihood of contrast-induced renal failure.
Bicarbonate and N-acetyl cysteine have been shown to decrease the risk of renal failure.
Ineffective preventive measures are diuretics such as furosemide or mannitol.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
290
Chapter 8 ● Nephrology
Clinical Recall
Which of the following lab values is seen in patients with prerenal azotemia?
BUN:Cr >20:1, Urine Na <20, FENa <1%, Urine Osmolality >500
BUN:Cr 10:1, Urine Na >40, FENa >1%, Urine Osmolality <350
BUN:Cr >20:1, Urine Na >40, FENa >4%, Urine Osmolality <350
BUN:Cr <10:1, Urine Na >40, FENa >1%, Urine Osmolality <500
BUN:Cr >20:1, Urine Na <20, FENa >4%, Urine Osmolality <350
Answer: A
GLOMERULONEPHRITIS
Glomerulonephritis (GN) is inflammation of the glomerulus, often as the result of an autoim- mune event, circulating antibodies, or vasculitis. Diabetes and hypertension cause glomerular disease and are certainly the most common causes of nephrotic syndrome and end-stage renal disease. They do not, however, have the acute inflammatory stage of glomerulonephritis characterized by hematuria.
All forms of GN can be characterized by edema, hematuria, red cell casts, and hypertension. The red cells develop an abnormal shape as they squeeze through the abnormal glomerulus (called “dysmorphic.”)
The edema of GN is found first in areas of low tissue tension, such as the periorbital area or scrotum. When more severe, edema can be found anywhere. With the salt and water retention leading to edema, hypertension also develops.
GN is characterized by modest amounts of protein in the urine, with a daily total <2 grams per 24 hrs, although by definition nephrotic syndrome does not begin until
GN is also characterized by low urine sodium, with fractional excretion of sodium <1%.
The most important distinction between GN and nephrotic syndrome is the degree of proteinuria.
Many, but not all, forms of GN have a characteristic blood test such as ANCA, basement membrane antibodies, ANA, or antistreptolysin. However, the single most important test for diagnosing GN is the renal biopsy. Unlike in tubular diseases, the renal biopsy is extremely important in GN because it guides therapy.
There are few treatments which can reverse a form of ATN based on the specific etiology. How- ever, with GN there are cytotoxic medications to use such as cyclophosphamide, or other treat- ments such as mycophenolate for SLE nephritis or plasmapheresis for Goodpasture syndrome. Hence, before committing a patient to long-term therapy with a potentially harmful medication (cyclophosphamide causes hemorrhagic cystitis), be sure to obtain a precise diagnosis.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
291
USMLE Step 2 l Internal Medicine
Note
Wegener granulomatosis is now called granulomatosis with polyangiitis (Wegener).
Table 8-2. Causes of Glomerulonephritis Disease Spectrum
Vascular Disease | Glomerular Disease |
Wegener granulomatosis (now called granulomatosis polyangiitis) | Goodpasture syndrome |
Churg-Strauss syndrome | Postinfectious glomerulonephritis |
Henoch-Schönlein purpura | IgA nephropathy (Berger disease) |
Polyarteritis nodosa | SLE |
Thrombotic thrombocytopenic purpura (TTP) | Idiopathic rapidly progressive glomerulonephritis |
Hemolytic uremic syndrome (HUS) | Alport syndrome |
Diabetes and hypertension (most common causes) | |
Wegener granulomatosis (WG) is characterized by systemic vasculitis that most often involves the kidney, lung, and upper respiratory tract such as the sinuses or middle ear. It can also involve the skin (50%), joints, eyes (50%), and GI tract. Neuropathy may be a symptom. If a patient with chronic upper and lower respiratory illness does not respond to antibiotics, con- sider WG. If there is renal disease as well, then WG is the most likely diagnosis.
Lab abnormalities include elevated ESR, anemia, and leukocytosis.
These findings are rather nonspecific and could be found in almost any vasculitis or chronic infectious/inflammatory condition. The best initial test specific is the anti- proteinase-3 antibody (or cytoplasmic antineutrophil cytoplasmic antibody
[C-ANCA]). The perinuclear pattern, or P-ANCA (or anti-myeloperoxidase antibody) is found in a much smaller number.
Complement levels are normal in WG.
The most accurate test is a biopsy of the kidney, nasal septum, or lung, looking for granulomas. Sinus biopsy, specifically the nasal septum, is less sensitive and has more false-negative results.
Treatment for WG is cyclophosphamide and steroids.
Churg-Strauss Syndrome
Churg-Strauss syndrome (CS) is a vasculitis similar to Wegener granulomatosis, and also charac- terized by chronic lung involvement, neuropathy, skin lesions, GI, cardiac, and renal involvement. All forms of vasculitis are characterized by fever, weight loss, and a generalized malaise. CS is characterized by a history of asthma, eosinophilia, and other atopic diseases. Diagnosis requires
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
292
Chapter 8 ● Nephrology
elevated eosinophils and positive P-ANCA. The most accurate test is a lung biopsy showing the granulomas and eosinophils.
Treatment is cyclophosphamide and glucocorticoids.
Goodpasture Syndrome
Goodpasture syndrome (GP) is an idiopathic disorder of renal and lung disease characterized by a unique antibasement membrane antibody. Unlike Wegener or Churg-Strauss, GP does not affect multiple organs or sites in the body besides the lung and kidney. Hence, the absence of skin or eye findings is a clue to the diagnosis.
About 35% of patients have no lung involvement and present only with hematuria and proteinuria.
When there is lung involvement, it is characterized by hemoptysis, cough, and shortness of breath. There will be hemosiderin-laden macrophages, cells that phagocy- tose free hemoglobin in the lung where it is metabolized to hemosiderin.
The best initial test to confirm the diagnosis is the level of antibasement membrane antibodies to type IV collagen. The single most accurate test is lung or kidney biopsy, which will show linear deposits on immunofluorescence.
Treatment is plasmapheresis and steroids. Cyclophosphamide may also help.
Polyarteritis Nodosa
Polyarteritis nodosa (PAN) is a systemic vasculitis of small- and medium-sized arteries that affects virtually every organ in the body except the lung. Renal involvement is common and manifests as hypertension, renal insufficiency, and hemorrhage due to microaneurysms. The most accurate diagnostic test is a biopsy.
Like all vasculitides, PAN is associated with fever, weight loss, and malaise.
Like WG and Churg-Strauss, there is involvement of the skin, eyes, muscles, GI tract, heart, kidneys, and neurologic system.
Although the liver is involved, there is usually no clinically evident hepatic effect.
Hepatitis B is seen in 10–30% of patients (especially injection drug users).
Abdominal pain and joint pain may be prominent. The abdominal pain may mimic mesenteric ischemia, and the pain will occur with eating. In that case, an angiogram of the involved vessels in the GI tract may eliminate the need for a biopsy. The sural nerve is a frequent location for the biopsy.
Anemia and an elevated sedimentation rate are present but are too nonspecific to be useful diagnostically.
P-ANCA is only present in a minority of patients. Treatment of PAN is with steroids and cyclophosphamide.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
293
USMLE Step 2 l Internal Medicine
Note
IgA nephropathy is the most common glomerulopathy worldwide.
IgA Nephropathy (Berger Disease)
IgA nephropathy presents with mild hematuria that resolves spontaneously in 30% of patients. About 40–50% of patients progress to end-stage renal disease. Like HSP, this is a disorder of the deposition of IgA; however, symptoms arise only from the kidney. Hypertension is frequent, most likely secondary to abnormally increased salt and water retention by the kidney.
Look for an Asian patient age <35 who has had a recent viral illness or pharyngitis and then develops hematuria 1–2 days later (“synpharyngitic”). (This is to distinguish it from poststrepto- coccal glomerulonephritis, where the renal involvement occurs 1–2 weeks later or longer.) Although this is an IgA deposition disease, blood IgA levels are elevated in only 50% of patients. Complement levels are normal. Diagnosis is based on finding on biopsy the IgA deposited in the kidney.
There is no proven treatment for IgA nephropathy. In the presence of proteinuria, give ACE inhibitors or angiotensin receptor blockers (ARB). If the proteinuria is massive, try steroids. The value of fish oil is marginal. The presence of proteinuria and hypertension imply a worse course.
Postinfectious Glomerulonephritis
In addition to group A beta hemolytic streptococci (Streptococcus pyogenes), numerous other infections can be associated with postinfectious glomerulonephritis. Virtually any infectious agent can cause it, including hepatitis B and C, CMV, and chronic staphylococcal infections such as endocarditis. In the pre-antibiotic era, glomerulonephritis was the most common cause of death in endocarditis.
Poststreptococcal glomerulonephritis (PSGN) can occur with either throat or skin infection with Streptococcus pyogenes, although rheumatic fever only occurs with the strains that cause pharyngitis. PSGN occurs in about 10–15% of patients with pharyngitis infected with a neph- ritogenic strain.
Presentation includes smoky, cola, or tea-colored urine, due to hematuria, red cell casts, and proteinuria.
The best initial tests are the antistreptolysin (ASO) and antihyaluronic acid (AHT) tests.
The most accurate test is the renal biopsy showing “humps” on electron microscopy. IgG and C3 will be deposited in the mesangium as subepithelial humps.
Treatment is largely supportive, with management of the fluid overload and hypertension with diuretics. Most cases resolve spontaneously, so biopsy is rarely needed. Give antibiotics to eradicate the organism from the pharynx.
Cryoglobulinemia
Renal disease from cryoglobulinemia is associated with chronic hepatitis C, and less com- monly, hepatitis B. Besides the renal disease, cryoglobulinemia is associated with joint pain, neuropathy, and purpuric skin lesions. This is similar to other types of vasculitis. There is no GI involvement as there is with Henoch-Schönlein purpura. Cryoglobulinemia is associated with elevated ESR and low levels of complement. Diagnosis is confirmed with a test for the cryoglobulins. A positive rheumatoid factor is a marker for the disease as well.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
294
Chapter 8 ● Nephrology
Treatment is management of the underlying chronic hepatitis. For severe disease, use pulse doses of steroids and occasionally plasmapheresis.
Diabetes
The incidence of glomerular involvement in diabetes is directly proportional to the duration of the diabetes. The standard dipstick becomes positive for albumin at a level 150–300 mg per 24 hrs of excretion. Microalbuminuria is a level of protein excretion that is abnormal but is <300 mg. If albumin is not present on dipstick, screen all diabetic patients annually for both microal- buminuria and serum creatinine.
Treatment for albuminuria is an ACE inhibitor or ARB. The BP goal is also lower in diabetes, and 130/80 mm Hg is optimal. Although a renal biopsy is the most accurate test for renal involvement in diabetes, it is not routinely performed unless there is the possibility of another disease causing the renal failure.
SLE
SLE is associated with an enormously wide variation in the degree of renal involvement. There may be asymptomatic proteinuria or hematuria, or there may be severe renal disease requiring dialysis. Double-stranded DNA levels go up and complement levels go down as a marker of severity in flare-ups of the disease. The most accurate test is a biopsy. Biopsy is essential with lupus nephritis in order to guide therapy.
Treatment is not needed for sclerosis; it is simply scarring of the kidney. For proliferative disease however, use steroids combined with mycophenolate. Mycophenolate is superior to cyclophosphamide and has fewer side effects.
Alport Syndrome
Alport syndrome is the combination of glomerular disease with congenital eye and ear abnormalities. There is sensorineural hearing loss.
Idiopathic Rapidly Progressive Glomerulonephritis
RPGN may occur with any of the glomerular diseases, in which case it simply refers to a time course of the disease. There is also an idiopathic form associated with crescent formation in the kidney and the presence of ANCA negative. Diagnosis is with renal biopsy. Treatment is steroids and cyclophosphamide.
Amyloidosis
There are 2 common types of amyloidosis:
Amyloid light-chain (AL): plasma cell dyscrasia causing deposition of protein derived from immunoglobulin light chains; may be associated with multiple myeloma
Amyloid A (AA): amyloid is produced as a proteinaceous material in association with a chronic infectious or inflammatory condition such as RA, IBD, or myeloma
– The amyloid protein builds up in the kidney, causing glomerulonephritis, and in the GI tract, nerves, and muscles.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
295
USMLE Step 2 l Internal Medicine
Maltese Cross Shape (Urinalysis) Seen in Nephrotic Syndrome
In the heart, amyloid is associated with restrictive cardiomyopathy, rhythm disorders, and heart block.
A large tongue (macroglossia) is also characteristic.
Neural involvement produces carpal tunnel syndrome.
Malabsorption may occur from GI involvement.
Diagnosis of amyloidosis is established with biopsy of an involved organ such as the kidney. Other unique methods of diagnosis are aspirating the abdominal fat pad or taking a sample of the rectum. Congo red testing shows green birefringence.
Treatment is very difficult and involves controlling the underlying disease. Melphalan and prednisone can control protein production.
Nephrotic syndrome refers to the severity of glomerular disease and does not, by itself, imply one specific etiology. It is defined as the presence of renal disease sufficient to produce a level of proteinuria >3.5 grams per 24 hrs, hyperlipidemia, edema, and low serum albumin. The edema is due to increased salt and water retention by the kidney, as well as low oncotic pres- sure in the serum. Hyperlipidemia is of unclear etiology but is most likely from the loss of the lipoprotein markers or signals on the surface of chylomicrons and LDL that lead to the clear- ance of these lipids from the bloodstream.
About 35% of nephrotic syndrome is associated with a systemic disease, e.g., diabetes, hypertension, or amyloidosis.
Patients with any glomerulonephritis-associated disease may develop nephrotic syndrome. When the glomerular basement membrane loses its negative charges, protein is spilled into the urine. If the severity of disease is bad enough, it will lead to massive proteinuria and low serum albumin.
Nephrotic syndrome is associated with hyperlipiduria, which gives a droplet found on urinalysis with a Maltese cross shape.
Patients can develop spontaneous arterial or venous thrombosis.
Iron, copper, and zinc deficiency may be present as a result of the urinary loss of their transport proteins such as transferrin and ceruloplasmin.
Diagnosis of nephrotic syndrome is based on the presence of high protein in the urine, low protein in the blood, edema, and hyperlipidemia. The 24-hour urine shows >3.5 grams of protein; however, this test is cumbersome to perform. An easier test with equal accuracy is a single spot urine for albumin and creatinine. When you correct the albumin level in a single spot urine, the ratio that is found is equivalent to the 24-hour urine. In other words, if a protein:creatinine ratio >3.5 is seen on a single urine, that is equal to 3.5 grams of protein on a 24-hour urine.
Remember that routine urine dipstick only detects albumin and not Bence-Jones protein (that must be done with urine immune electrophoresis).
The most accurate test for determining the specific etiology of nephrotic syndrome is renal biopsy.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
296
Chapter 8 ● Nephrology
Treatment of nephrotic syndrome is control of the underlying disease. In addition, steroids are used to treat all forms of idiopathic primary renal causes of nephrotic syndrome, such as membranous, nil lesion, membranoproliferative, mesangial, and focal-segmental disease. If steroids do not work, add cyclophosphamide or mycophenolate. Azathioprine may be useful. ACE inhibitors or ARBs are used for all patients with proteinuria, but they do not reverse the underlying disease.
All of the following syndromes are diagnosed as described and treated with steroids and sometimes cyclophosphamide or mycophenolate.
Focal-Segmental Glomerulosclerosis (FSGS). Associated with the use of heroin as well as HIV. Limited response (only 20–40%) to steroids. May progress to end stage renal disease (ESRD) over 5–10 years. FSGS is the most common cause of nephrotic syndrome in adults.
Membranous. Associated with cancer such as lymphoma or breast cancer, and infections such as endocarditis or chronic hepatitis B or C. Other etiologies are lupus, penicillamine, gold salts, and NSAIDs. Most are idiopathic.
Nil Lesion (Minimal Change Disease). Most common form in children, although it may account for 15% of adult disease. NSAIDs have also been associated with nil lesion disease. Light micros- copy is normal and electron microscopy is needed to see fusion of foot processes. Nil lesion disease is treated with steroids. Hodgkin’s lymphoma has an association with nil lesion disease.
Mesangial. Mostly idiopathic, steroid-resistant type of nephrotic syndrome. Immuno- fluorescent staining shows IgM deposits in an expanded mesangium.
Membranoproliferative. Associated with chronic hepatitis and low serum complement levels. Dipyridamole and aspirin are also useful therapeutically. Must treat underlying disease.
Clinical Recall
Which of the following is the most accurate diagnostic test for Wegner’s granulomatosis?
Lung and nasal septum biopsy showing granulomas
Kidney biopsy revealing IgA deposits
Renal biopsy showing “humps” on electron microscopy
Answer: C
DIAGNOSTIC TESTING IN RENAL DISEASE
Urinalysis
There is no recommendation for routine testing of the general population by urinalysis. Diabetics or those with systemic diseases such as hypertension are not the general population.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
297
USMLE Step 2 l Internal Medicine
Proteinuria. The urine dipstick detects albumin but no other protein, such as immunoglobulin light chains. It can be caused by glomerular or tubular disease, although glomerular disease can give greater amounts. Microalbuminuria is defined as levels 30–300 mg per 24 hours. Mild amounts of proteinuria <1 gram per day can be seen in up to 10% of the population and most often resolve spontaneously. Proteinuria can also occur from stressors such as fever, CHF, and severe exercise.
Proteinuria can also caused by prolonged standing (known as orthostatic proteinuria, consid- ered benign). To confirm diagnosis, split the 24-hour urine sample: no protein will be found in the first 8 hours, but it will be found in the second period.
Hematuria. Red cells can be found in the urine from any cause of disease in the bladder or kidney. Etiologies are stones, cancer, bleeding disorders, trauma to urinary system, and treatment such as cyclophosphamide (which causes hemorrhagic cystitis or glomerular disease). Hematuria is also from infections such as cystitis or prostatitis. The red cells change shape in glomerular disease and can be dysmorphic.
Nitrites. Gram-negative bacteria reduce nitrate to nitrite, which is a marker of infection.
Bacteriuria. By itself, the isolated finding of bacteria in the urine is of very limited significance. The most important exception is in pregnant women, whom you should screen for bacteria and treat. About 30% of pregnant women with bacteriuria progress to pyelonephritis.
Dehydration. These casts develop as an accumulation of the normal amount of tubular protein. They do not necessarily mean disease. | |
Also called “dirty” or “muddy.” They are associated with acute tubular necrosis and represent accumulated epithelial cells. | |
298
END-STAGE RENAL DISEASE/DIALYSIS
The most common causes of end-stage renal disease (ESRD) requiring dialysis are diabetes and hypertension. The next most common cause is glomerulonephritis (15% of cases), followed by cystic disease and interstitial nephritis (each 4–5%).
The indications for dialysis are life-threatening abnormalities that cannot be corrected another way:
Fluid overload refractory to diuretics
Acidosis
Pericarditis
Encephalopathy
Severe neuropathy such as myoclonus, wrist/foot drop, hyperkalemia
Persistent nausea, vomiting, and bleeding diathesis attributable to uremia
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
Chapter 8 ● Nephrology
Hemodialysis is used in 85% of patients and peritoneal dialysis in 15%. The most common complication of peritoneal dialysis is peritonitis. Other complications include:
Anemia from the loss of production of erythropoietin from the kidney. The anemia is treated with erythropoietin replacement. The anemia of ESRD is normochromic and normocytic.
Hypocalcemia/hyperphosphatemia from the loss of 1,25-dihydroxyvitamin D production. The hypocalcemia is treated with vitamin D replacement. Hyperphospha- temia is from the inability of the kidney to excrete phosphate. High phosphate levels contribute to low calcium levels by precipitating out in tissues in combination with the calcium. High phosphate level is treated with phosphate binders, such as calcium carbonate or calcium acetate.
Aluminum-containing phosphate binders should not be used, as aluminum is associated with CNS accumulation, dementia, and bone abnormalities.
Sevelamer and lanthanum are phosphate binders that do not contain aluminum or calcium. Use when calcium is abnormally high due to vitamin D replacement.
Cinacalcet is a substance that simulates the effect of calcium on the parathyroid; it will tell the parathyroid to shut off parathyroid hormone production, thus helping to decrease phosphate. Use in severe, refractory cases.
Osteodystrophy (or osteitis fibrosa cystica). Bone abnormalities occur because dead kidneys do not make 1,25 vitamin D. This leads to a low calcium level. The low calcium leads to secondary hyperparathyroidism, which removes calcium from the bones. In addition, bones buffer acidosis by removing calcium from bone. When you want to demineralize a piece of bone in a lab, you soak it in acid; this is what is happening in the body. Renal osteodystrophy is controlled with improving calcium and phosphorous levels and treating the secondary hyperparathyroidism.
Hypermagnesemia. Magnesium accumulates because of decreased renal excretion. Treatment is by restricting magnesium intake.
Hypertension and accelerated atherosclerosis. Renal disease results in a rapidly progressive coronary artery disease. The reason for this is not precisely clear, however, this is the most common cause of death for those on dialysis. This is why the goal of blood pressure management is lower at 130/80 mm Hg for those with renal impair- ment.
Infection. ESRD patients are at increased risk of infection because neutrophils and other white cells do not work normally in a uremic environment. This is the second most common cause of death in dialysis patients. The most common organism is Staphylococcus because of the constant need to penetrate the skin to place someone on dialysis for 4–6 hours 3–4 times a week.
Bleeding. Although nephrotic syndrome gives thrombophilia because of the urinary loss of protein C, protein S, and antithrombin, the most common coagulation problem with ESRD is bleeding. This is because of uremia-induced platelet dysfunction. It gives an increased bleeding time. Uremia-induced bleeding is treated with desmopressin, which releases subendothelial stores of von Willebrand factor and factor VIII, which increase platelet aggregation and adherence. Rarely, estrogen or cryoprecipitate are used.
Treatment. Those with severe renal disease should restrict potassium, sodium, protein, magnesium, and phosphate in their diets.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
299
USMLE Step 2 l Internal Medicine
Other abnormalities associated with ESRD are pruritus, hyperuricemia, decreased libido from low testosterone levels, weakness, fatigue, and glucose intolerance. Although not life threaten- ing, they do have a significant impact on function. The only way to improve them is with dialysis, although, by themselves, they are not indications for dialysis (the indications for dialysis are hyperkalemia, acidosis, fluid overload, encephalopathy, and pericarditis).
RENAL TRANSPLANTATION
The duration of survival is by far superior with transplantation when compared with mainte- nance on dialysis.
Live related donor: 95% at 1 year; 72% at 5 years
Cadaver donor: 88% at 1 year; 58% at 5 years
Dialysis alone: 30–40% at 5 years
Diabetics on dialysis: 20% at 5 years
The average wait to obtain a kidney for transplantation is 2–4 years and becoming longer because of an insufficient donor supply.
Post-transplantation renal graft rejection is prevented by using cyclosporine, tacrolimus, corticosteroids, and mycophenolate. These are all medications which inhibit T-cell function.
FLUID AND ELECTROLYTE DISORDERS
Hyponatremia is low serum sodium concentration <135 mEq, generally as a result of increased free water retention or urinary sodium loss. About 85–90% of sodium is extracellular. Serum osmolality is largely a function of the serum sodium level.
Serum osmolality = (2 × sodium) + BUN/2.8 + glucose/18 When glucose and BUN are normal, that roughly comes out to be 2 × sodium + 10.
Clinical Presentation. The symptoms of hyponatremia are predominantly neurologic. They range from mild confusion and forgetfulness to disorientation and obtundation to seizure or coma, depending on the severity. Symptoms do not correspond to a specific sodium level because they largely depend on how fast the level dropped. An acute 15–20 point drop in sodium can cause a seizure or coma. If the level drops gradually, there may be no symptoms at all (even to an extremely low sodium level). Generally, there should be no symptoms unless sodium <125.
Treatment.
Mild hyponatremia should resolve with fluid restriction. “Mild” refers to the absence of symptoms, not a specific level.
Moderate hyponatremia can be managed with normal saline administration combined with a loop diuretic such as furosemide. The saline gives sodium, and the loop diuretic causes a net free water loss.
Severe hyponatremia such as that resulting in seizure or coma should be managed with 3% hypertonic saline or the V2 receptor-antagonists conivaptan and tolvaptan. It would be unusual to see severe symptoms with sodium >120.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
300
Chapter 8 ● Nephrology
The rate of rise of the sodium level should be monitored so as not to cause central pontine myelinolysis. This is what occurs if the sodium level is corrected too rapidly. Generally, the rate of rise should not exceed 0.5–1 mEq per hour. This means no more than a 12-point rise in 12–24-hours. Hyponatremia can be corrected as rapidly as 2 mEq per hour if the patient is seizing and it is extremely urgent. Fludrocortisone is used for cerebral salt-wasting disease.
Specific etiologies
Hypervolemic states (increased ECF) are conditions in which there is a decrease in intravas- cular volume, resulting in an increase in ADH secretion from the posterior pituitary. This is a form of appropriate increased ADH syndrome.
CHF
Nephrotic syndrome and low albumin states
Cirrhosis
Renal insufficiency: When renal failure becomes advanced, the impaired free water excretion will drop the sodium level.
Hypovolemic states (decreased ECF) are conditions in which the hyponatremia develops because of the loss of sodium through body fluids and replacement with free water. For exam- ple, sweating is a cause of hypernatremia because sweat is mostly free water and only has a little sodium. However, when you sweat and replace only with free water, sodium drops over time.
Diuretics: you urinate out a little salt but replace with only free water
Renal sodium loss: The kidney can lose the ability to reabsorb sodium in the proximal convoluted tubule as the kidney is damaged. Damaged tubules cannot reabsorb sodium.
Adrenal insufficiency (Addison disease): Aldosterone reabsorbs sodium from the kidney. Without aldosterone, you lose sodium.
Table 8-4. Causes of Hypovolemic Hyponatremia
Urine Na <20 | Urine Na >20 |
Dehydration | Diuretics |
Vomiting | ACE inhibitors |
Diarrhea | Renal salt wasting |
Sweating | Addison disease |
Cerebral sodium wasting |
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
301
USMLE Step 2 l Internal Medicine
Euvolemic States. These patients are neither dehydrated nor volume overloaded. There is no edema, neither is there orthostasis or decreased skin turgor.
Psychogenic polydipsia: patients must drink at least 15–20 liters a day of fluid to overwhelm the diluting capacity of the kidney
Hypothyroidism: mechanism unknown
Diuretics: can be both hypovolemic and euvolemic
ACE inhibitors: probably through an increase in ADH
Endurance exercise
Syndrome of inappropriate secretion of ADH (SIADH)
Clinical Recall
Which of the following is not an indication for dialysis in end stage renal disease?
Answer: E
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) can be caused by CNS disease (infection, stroke, tumor, trauma, vasculitis, pain); pulmonary disease (pneumonia, TB, PE, asthma); or neoplastic disease (cancers of the lung, pancreas, duodenum, thymus).
SSRIs
Tricyclic antidepressants
Haloperidol
Cyclophosphamide
Vincristine
Carbamazepine
Thiazide diuretics
The presentation of SIADH is similar to all forms of hyponatremia in terms of neurologic symptoms in proportion to the degree of hyponatremia. Diagnosis is based on finding elevated urine osmolality and urine sodium. This is inappropriate to find in a patient with hyponatremia.
The range on urine osmolality is 50–1,200 mOsm/L. If urine osmolality >100 in the presence of hyponatremia, the person most likely has SIADH.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
302
Chapter 8 ● Nephrology
The single most accurate test is an elevated ADH, though it is rarely done and is inferred from the urine osmolarity.
Treatment of SIADH is fluid restriction (mild disease) and hypertonic saline (severe disease). Normal saline with a loop diuretic is also useful for raising the sodium level. For chronic disease in which the underlying cause of the SIADH cannot be corrected, use conivaptan, tolvaptan, or demeclocycline, which can inhibit the effect of ADH on the kidney tubule and lead to water diuresis. Conivaptan and tolvaptan are V2 receptor-antagonists. Demeclocycline and lithium treat SIADH by inducing nephrogenic diabetes insipidus. Lithium is rarely used, due to toxicity.
Hypernatremia
Insensible losses: extrarenal loss without intake of hypotonic fluids; increased skin loss (sweating, burns, fever, exercise) or respiratory infections
GI loss: osmotic diarrhea (e.g., lactulose, malabsorption), some infectious diarrhea
Transcellular shift: rhabdomyolysis or seizures causing muscles to avidly take up water and ↑Na
Renal
Nephrogenic diabetes insipidus (NDI), secondary to renal disease, increased calcium, decreased potassium, lithium, demeclocycline, sickle cell disease, and others
Central DI (CDI)
Idiopathic, trauma, infectious, tumor, granulomatous, hypoxic brain damage or from neurosurgery. Idiopathic most common.
Osmotic diuresis: diabetic ketoacidosis (DKA), nonketotic hyperosmolar coma, mannitol, diuretics
Clinical Presentation. Symptoms are primarily neurologic. With severe hypernatremia of any cause, lethargy, weakness, irritability, seizures, and coma are present. Diabetes insipidus gives a dilute diuresis of 3–20 L per day. For diagnosis, watching for a drop in urine volume after administering ADH will distinguish CDI from NDI.
Treatment. Treat acute hypernatremia with IV isotonic fluids. Correction of sodium should not be >1 mEq every 2 hours or 12 mEq per day. Complications of overly rapid correction include cerebral edema, permanent neurologic damage, or seizures. A rate of correction as fast as 1 mEq per hour is also acceptable if the patient is seizing.
CDI. Correct the underlying cause, if possible. Vasopressin (ADH) can be given subcutaneously, intravenously, intramuscularly, or by nasal spray (all routes except oral).
NDI. Correct underlying cause, if possible. Diuretic or NSAIDs can be given. NSAIDs work by inhibiting prostaglandins, which impair concentrating ability. NSAIDs will increase the action of ADH at the kidney.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
303
USMLE Step 2 l Internal Medicine
Hypokalemia
In hypokalemia, potassium levels are maintained by transcellular shift and rates of renal excre- tion. About 95% of potassium is intracellular. Hypokalemia may be caused by the following:
GI losses. from any form of GI loss, such as vomiting, diarrhea, or tube drainage
Increased entry into cells (transcellular shift): from alkalosis, increased insulin, beta adrenergic activity (increased in trauma patients, possibly leading to hypokalemia), and replacement B12 in B12-deficient patients
Urinary losses: from diuretics; low magnesium; increased aldosterone states (e.g., Conn syndrome, excessive licorice ingestion, Bartter syndrome, or Cushing disease)
Magnesium decreases urinary loss of potassium. When you are deficient in magnesium, you start to spill potassium into the urine.
Aldosterone is the most important regulator of potassium level in the body.
Renal artery stenosis results in a high renin/aldosterone state.
Symptoms of hypokalemia predominantly affect the muscles and the heart. Patients have weakness, paralysis (when it is severe), arrhythmias which can be fatal, and even rhabdomy- olysis. Potassium is necessary for ADH effect on the kidney, and hypokalemic patients present with nephrogenic diabetes insipidus. In emergency cases, the most important diagnostic test is the EKG; abnormalities will include T-wave flattening and U-waves. A U-wave is an extra wave after the T-wave that is indicative of Purkinje fiber repolarization.
Treatment. Correction of underlying cause when possible. Replete as follows:
IV maximum 10–20 mEq/h; do not use dextrose containing fluids, as they increase insulin release and lower potassium.
Oral: Gut regulates absorption; there is no maximum rate of oral potassium replace- ment.
GI tract slows absorption; no dextrose-containing fluids; dextrose brings increased extracellular potassium entry into cells.
Potential complication of too-rapid repletion is fatal arrhythmia.
Very large amounts of potassium may be necessary to raise the body potassium level by even 1 or 2 points. The total body requirement is to give 4–5 mEq per kg per point. Do not use IV fluids that contain dextrose, since dextrose will provide the shift of potassium into the cells and further reduce the potassium.
Hyperkalemia
Etiology
Increased intake (orally or by IV)—usually in presence of impaired excretion
Movement from cells to extracellular fluid (ECF)
Pseudohyperkalemia: secondary hemolysis, mechanical trauma during venipunc- ture, platelets >1,000,000 (106), WBCs >100,000 (105)
Acidosis: secondary cellular buffering (H+ moves into cells, K+ moves out)
For every 0.1-point decrease in the pH, the potassium level will increase by
0.7 points because of the transcellular shift
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
304
Chapter 8 ● Nephrology
Insulin deficiency
Tissue breakdown: rhabdomyolysis, tumor lysis after seizures or severe exercise
Periodic paralysis: mild, brief episodes of muscle weakness with mild increase in K+; diagnosis with recurrent attacks and family history
Decreased urinary excretion
Renal failure
Hypoaldosteronism: ACE inhibitors, type IV RTA, adrenal enzyme deficiency; heparin inhibits production of aldosterone
Primary adrenal insufficiency (Addison disease) or adrenalectomy
Potassium-sparing diuretics—amiloride, spironolactone
NSAIDs
Clinical Presentation. Muscular weakness can begin usually with K+ level >6.5. Abnormal cardiac conduction is the most common cause of death. Diagnosis includes peaked T waves, widened QRS, short QT, or prolonged PR on EKG.
Treatment
Calcium gluconate: membrane stabilization (most emergent treatment in presence of EKG abnormalities); effect is immediate and short-lived
Sodium bicarbonate: alkalosis drives K+ into cells (do not give in same IV line as calcium); forms CaCO3 precipitates
Glucose and insulin: drives K+ intracellular, takes 30–60 min to work
Cation exchange resin: resin absorbs 1 mEq K+ per g and releases 1 mEq Na+(give with sorbitol to prevent constipation); must be given with treatments above because they only cause cellular redistribution of K+ and do not remove from the body (also available as retention enema for those who cannot take orally)
Dialysis
Beta 2 agonists
ACID/BASE DISTURBANCES
Alkalosis (High pH)
Metabolic
For every 1-point increase in the level of serum bicarbonate, there is a 0.7-point increase in pCO2.
Volume contraction of dehydration results in increased aldosterone, which leads to metabolic alkalosis.
Increased aldosterone in volume contraction leads to increased hydrogen ion (H+) excretion.
Increased sodium delivery to the distal tubule leads to increased sodium reabsorption in a segment of the tubule that excretes H+ and K+.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
305
USMLE Step 2 l Internal Medicine
H+ Ion Loss
Exogenous steroids
GI loss (vomiting, nasogastric suction)
Renal loss (Conn syndrome, Cushing, ACTH overproduction, licorice, Bartter syndrome)
Decreased chloride intake
Diuretics
HCO3 Retention
Bicarbonate administration
Contraction alkalosis
Milk-alkali syndrome
Progesterone, catecholamines, hypoxia, cirrhosis, pregnancy, and salicylates are all events or substances which increase the respiratory rate and minute ventilation, and thus lead to respiratory alkalosis.
Anion gap = (Na+) - (HCO3 + Cl )
(normal 8–12)
Acidosis (Low pH)
Metabolic
Low Anion Gap
Myeloma
Low albumin level
Lithium
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
306
Chapter 8 ● Nephrology
The anion gap is a gauge of the unmeasured anions in the bloodstream. The majority of the unmeasured anions are usually albumin, which has a significant amount of negative charge. In addition to albumin, which is normal, the other anionic substances are lactate, ketoacids, and the metabolic end products of toxic alcohols.
3
Na+ and cations = HCO – and Cl– and anions
3
Hence, if the sodium and cations remain the same and the anions go up, then HCO – must go
down.
3
On the other hand, if the amount of cations goes up, that will lead to increased HCO – and Cl–. (That explains why there is a decreased anion gap in myeloma. Myeloma proteins are cationic. This leads to an increase in chloride and bicarbonate, and thus a decreased anion gap.)
A low albumin level does the same thing. For every 1-point decrease in albumin, there is a
point decrease in the anion gap. If albumin, the main unmeasured anion, goes down, then the levels of chloride and bicarbonate increase to assure electrical neutrality.
Lithium, magnesium, and calcium are all divalent cations that decrease the sodium level. If the sodium level drops and everything else remains the same, there will be a decreased anion gap. If sodium is lower, but bicarbonate and chloride stay the same, then the anion gap must decrease.
Normal Anion Gap
Increased Anion Gap
LA MUD PIE (Mnemonic) Lactate (sepsis, ischemia, etc.) Aspirin
Methanol Uremia
Diabetic ketoacidosis (DKA): Beta hydroxybutyric acid (BHB) and acetoacetate, which are formed from fatty acids, are an alternate fuel source because the cells cannot absorb glucose because there is a deficiency of insulin
Paraldehyde, Propylene glycol
INH
Ethylene glycol (antifreeze, low calcium)
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
307
USMLE Step 2 l Internal Medicine
Respiratory
Hypoventilation of any cause
Chronic obstructive pulmonary disease (COPD)
Pickwickian
Obesity
Suffocation
Opiates
Sleep apnea
Kyphoscoliosis
Myopathies
Which of the following treatments for hyperkalemia removes potassium from the body?
Answer: C
RENAL TUBULAR ACIDOSIS
Distal (Type I)
Distal renal tubular acidosis (RTA) is usually sporadic. It is secondary to autoimmune disease (e.g., Sjögren syndrome, SLE). Causes may include:
Drugs: amphotericin, lithium, analgesics, ifosfamide
Nephrocalcinosis, sickle cell, chronic infection
Familial
Chronic hepatitis
Clinical Presentation. Patients are unable to develop a high H+ concentration in urine. Urine pH is >5.3. There is secondary hyperaldosteronism and hypokalemia, as well as nephrocalcinosis and nephrolithiasis. Patients may get kidney stones.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
308
Chapter 8 ● Nephrology
To diagnose, use the acid load test. Give ammonium chloride, which should lower urine pH secondary to increased H+ formation. With type I RTA, urine pH remains elevated. Serum bicarbonate is 10.
Patients with type 1 RTA develop hypokalemia because they lose their ability to secrete hydrogen ions or H+. Instead of excreting H+, the kidney excretes K+.
Urine anion gap is a way to distinguish whether the etiology of a normal anion gap metabolic acidosis is diarrhea or distal RTA.
Diarrhea: Metabolic acidosis with intact ability to excrete acid. The NH4Cl level will be high in urine. The urinary anion gap will be negative.
RTA: Kidneys cannot excrete acid in the urine. The urine NH4Cl level will be low. The urinary anion gap will be positive.
Treatment. Treat with oral bicarbonate because its reabsorption in the proximal tubule still works. Also give potassium replacement; potassium citrate will replace both bicarbonate as well as potassium in distal RTA. Citrate is an effective calcium stone antagonist.
Proximal (Type II)
Proximal RTA is a result of Fanconi syndrome, Wilson disease, amyloidosis, myeloma, acetazolamide, vitamin D deficiency, secondary hyperparathyroidism, chronic hypocalcemia, heavy metals, chronic hepatitis, or autoimmune disease such as SLE or Sjögren syndrome.
Clinical Presentation. Patients are unable to absorb bicarbonate. The initial urine pH is basic (until the body loses enough bicarbonate that it is within the range of absorption of the distal tubule), then the urine becomes acidic (pH <5.4). Patients also present with hypokalemia and serum bicarbonate 18–20, as well as proximal tubule leak of glucose, phosphate, urate, amino acids.
Patients may get bone lesions (osteomalacia and rickets). To diagnose, patients will be unable to absorb bicarbonate loading (sodium bicarb IV) and have a basic urine in the presence of acidemia. (Normal individuals do not excrete bicarbonate in the urine until serum bicarbonate >24.)
Treatment. Give potassium phosphate; mild volume depletion will enhance proximal bicar- bonate reabsorption (a type of contraction alkalosis). Thiazide diuretics and very large amounts of bicarbonates are used. Bicarbonates are generally ineffective, explaining why such high amounts must be used. Bicarbonate administration increases renal potassium loss.
Hyporeninemic/Hypoaldosteronism (Type IV)
Hyporeninemic/hypoaldosteronism RTA is an aldosterone deficiency of any cause or adrenal insensitivity to angiotensin II, which normally stimulates aldosterone release. Causes include:
Diabetes (50%)
Addison disease
Sickle cell disease
Renal insufficiency
Medications
Clinical Presentation. Patients usually present with asymptomatic hyperkalemia; mild to moderate renal insufficiency; and hyperchloremic metabolic acidosis (nonanion gap). The presence of high urine sodium with oral salt restriction establishes the diagnosis.
Note
Hypokalemia is common in both type 1 and type 2 RTA patients.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
309
USMLE Step 2 l Internal Medicine
Treatment. Treat with fludrocortisone, which has a strong mineralocorticoid effect and is similar to administering aldosterone. Loop diuretics will lower potassium.
NEPHROLITHIASIS
Nephrolithiasis is seen in 1–5% of the population. Causes include:
Composition of stones
Calcium oxalate 70%
Calcium phosphate 10%
Mg/aluminum/phosphate (struvite) 5–10%
Uric acid 5%
Cysteine 1%
Increased absorption: vitamin D intoxication; increased vitamin D with sarcoid and other granulomatous disease; familial
With fat malabsorption, the fat binds to calcium, leaving oxalate to be reabsorbed in increased amounts.
Citrate usually binds with calcium and prevents calcium absorption. Low citrate leads to an increase in calcium absorption. Causes of hypocitraturia include any acidotic condition.
Uric acid stones
They form in an acid environment and are associated with diseases like gout, hematologic malignancies, and Crohn’s disease. Radiolucent on x-ray.
Cystinuria
Only associated with the genetic disorder.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
310
Chapter 8 ● Nephrology
Infection
Urinary infection with urease-producing organisms such as Proteus, Pseudomonas, and
Klebsiella give a highly alkaline urine that produces struvite stones.
Clinical Presentation. Patients present with constant flank pain (not colicky), hematuria, and pain radiating to the groin. Stones <5 mm should pass spontaneously. Diagnosis is made with the following:
Plain x-ray (rarely used) (80% yield)
U/S: high-yield test and most cost-effective
Strain the urine for stones
Check serum and urine calcium
IV pyelogram: always wrong
Helical (spiral) CT scan: no contrast needed for stones; contrast is to identify masses, abscesses, and tumors; high-yield test
Treatment. Analgesia, hydration, and bed rest are the mainstays of treatment.
Shockwave lithotripsy for stones <2 cm (unfortunately, the fragments may cause obstruction themselves)
Ureteroscopy
Percutaneous removal (requires more anesthesia and hospital stay)
Nifedipine and tamsulosin: may expel borderline-sized stones 5–7 mm
Adult Polycystic Kidney Disease
Adult polycystic kidney disease is often genetic (prevalence 1:200 to 1:1,000). Pathogenesis is complex.
Clinical Presentation.
Flank pain, hematuria (micro and gross), infections, and calculi
May also present as asymptomatic on screening of family members
Extra-renal manifestations: hepatic cysts (40–60%); colonic diverticula; hypertension (50%); intracranial aneurysm (10–20%) (other vascular aneurysms may be seen); mitral valve prolapse (25%)
Diagnose with U/S and CT scan. Treatment is nonspecific; manage the complications (UTI, calculi, and hypertension).
Simple Cysts
Simply cysts are very common. If they are smooth-walled with no debris inside the cyst, they can be managed without further treatment or diagnostic tests. If they have irregular walls or debris inside, follow closely to exclude malignancy. Dialysis causes cysts.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
311
USMLE Step 2 l Internal Medicine
Note
Some guidelines have recommended diagnostic values of 130/80 mm Hg for patients with diabetes or chronic kidney disease. However, the clinical benefits of this lower target have not been established, so treat these patients to <140/90 mm Hg.
HYPERTENSION
Essential Hypertension
An estimated 50 million Americans have high blood pressure (BP). Essential hypertension accounts for >95% of all cases of hypertension. Despite multiple theories on the mechanism, there is no clear understanding of what causes essential hypertension.
More common with increasing age; is found in 50% of those age >60
More common in men than women until after menopause
More common in black population at all ages, as is incidence of end-organ damage
Onset usually age 25–55
Hypertension is diagnosed when systolic BP is 140 mm Hg or diastolic BP is ≥90 mm Hg (or both) on repeated examination. Systolic BP is particularly important, and is the basis for diagnosis in most patients. These numbers apply to all adults age >18 (although for those age
≥80, systolic BP up to 150 mm Hg is now regarded as acceptable). The goal for treatment of hypertension is to reduce BP to levels below the numbers used for making the diagnosis.
Patients with very severe hypertension (BP >160/100 mm Hg) should receive initial therapy with 2 medications, as 1 medication will not be sufficient.
Clinical Presentation. The most common presentation of essential hypertension is an asymp- tomatic patient on whom elevated BP is found during a routine examination or evaluation for other medical problems. When symptoms are associated with hypertension, think of them as follows:
Acute symptoms associated with a hypertensive emergency OR
Complications from end-organ damage
With hypertensive emergency, signs and symptoms of cardiac, neurologic, renal, and retinal involvement are the most common. These include evidence of stroke, subarachnoid hemor- rhage, encephalopathy, myocardial ischemia, and abnormalities on fundoscopic examination. Requires substantial reduction of blood pressure within 1 hour to avoid serious morbidity or death. These can acutely and most commonly result in headache, dizziness, chest pain, dyspnea, blurred vision, and palpitations. Malignant HTN is defined as encephalopathy or nephropathy with accompanying papilledema as seen on funduscopic examination.
Long-Term Complications
Cardiac: myocardial ischemia or infarction, CHF, left ventricular hypertrophy, aortic aneurysm, and dissection, on physical exam an S4 gallop, accentuated A2 heart sound, and prominent left ventricular impulse can be present
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
312
Chapter 8 ● Nephrology
Cerebrovascular: transient ischemic attack (TIA) or stroke
Renal proteinuria: microscopic hematuria, and elevation of BUN/creatinine, which may require dialysis
Retinopathy: hemorrhages, exudates, arteriolar narrowing, and papilledema; they result in blurred vision, scotomata, and sometimes blindness
With secondary hypertension (<5% of patients), the presentation depends upon the cause.
Renovascular disease causes an abdominal bruit.
Cushing disease causes weight gain, moon-like facies, striae, and ecchymoses.
Pheochromocytoma causes episodic hypertension associated with headache, palpita- tions, and sweating
Primary aldosteronism (Conn syndrome) causes muscular weakness and polyuria/ polydipsia from hypokalemia.
Diagnosis. As much as 20–25% of mild office hypertension is artifactual in nature. These initial elevated readings merely represent a manifestation of anxiety on the part of the patient to the doctor and medical environment (known as “white coat hypertension”). These are patients have no evidence of end-organ damage.
When patients are given time to sit and adjust to the environment before the reading is taken, their pressure will lower. If they are able to measure their own pressure at home with an ambulatory pressure-monitoring device, many of them will produce normal pressure. With each subsequent visit to the physician, the patient’s pressure will likely lower toward its true value. Therefore, prior to diagnosing a patient with mild elevation as truly hypertensive, take the following steps:
Allow the patient to sit quietly for 5 minutes before pressure is measured
Never label a patient as hypertensive after only a single reading
Repeat the reading 3–6 times over several months before confirming the diagnosis and initiating therapy
Most routine lab testing will be normal. Testing is usually kept within the bounds of those done during a routine medical evaluation. The purpose is to evaluate the extent of end-organ dam- age as well as to exclude some forms of secondary hypertension. Basic studies include:
Urinalysis for protein, glucose, RBCs, and casts
Hematocrit
Serum potassium to exclude hyperaldosteronism
Serum creatinine and BUN
Electrocardiogram to evaluate for left ventricular hypertrophy
Glucose and plasma lipid analysis as an indicator of atherosclerotic risk
Treatment. Treat confirmed mild and moderate hypertension with nonpharmacologic modifications in lifestyle: weight loss for the obese, dietary sodium restriction, aerobic exercise, reduced alcohol intake, and low-fat diet with increased dietary fiber (DASH “Dietary Approaches to Stop Hypertension” diet includes increased fruits/vegetables, low-fat dairy).
Relaxation methods have inconsistent effects.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
313
USMLE Step 2 l Internal Medicine
Note
There is a linear correlation of increasing weight with
increasing BP. Obesity further
increases CV risk by increasing LDL, decreasing HDL, and decreasing glucose tolerance.
For every kilogram of weight lost, there is generally a 0.5–1.0 mm Hg drop in systolic and diastolic BP.
Note
With hypertension, try to individualize therapy based on the patient’s findings. To do so, you must be familiar with the characteristics of each class of drugs.
Note
Malignant and accelerated HTN are difficult to distinguish clinically. Malignant is usually more severe, with encephalopathy or nephropathy and accompanying papilledema as seen on funduscopic examination. Cause is unknown.
Treat severe hypertension (diastolic >100 mm Hg) immediately with drug therapy, using 2 medications as initial therapy for those with BP >160/100 mm Hg.
Patients who continue to have diastolic BP >90 mm Hg after 3−6 months of nonpharmacologic therapy should be started on an antihypertensive drug. The decrease in end-organ damage, such as myocardial infarction and stroke with drug treatment, is generally greater in those who have a higher baseline BP. In other words, someone with diastolic pressure >100 will show a much greater reduction in risk of stroke with drug therapy than someone whose diastolic pressure is 90–95 mm Hg.
There are almost 50 medications approved for the initial treatment of hypertension, not including combination medications.
In the absence of a specific indication or contraindication, diuretics are still recom- mended as initial treatment (their mortality benefit is unsurpassed).
For stage III HTN, BP >160/100, use a 2-drug combination: diuretic plus ACE inhibitors/ARB/CCB or beta blocker.
If diuretics do not control the BP, add a second medication: ACE inhibitors/ARB/ CCB or beta blocker.
Consider the following when treating specific hypertensive groups:
In the general nonblack population, including those with diabetes, initial antihyper- tensive treatment should include a thiazide-type diuretic, calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEI), or angiotensin receptor blocker (ARB).
Treat those who have postmyocardial infarction (ischemic heart disease) with beta blockers.
Treat those who have diminished left-ventricular systolic function (i.e., in CHF or postmyocardial infarction) with ACE inhibitors and/or beta blockers.
Treat pregnant patients with alpha-methyldopa, labetalol, hydralazine, or CCBs. ACE inhibitors and ARBs are absolutely contraindicated. Diuretics are relatively contra- indicated.
African-American patients are least effectively treated with ACE inhibitors.
Clinical Recall
A 48-year-old man comes to the clinic with blood pressure 150/95 mm Hg. What is the best initial therapy?
Hydrochlorothiazide
Lifestyle modification and chlorthalidone
Lisinopril
Atenolol
Amlodipine
Answer: B
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
314
Chapter 8 ● Nephrology
Hypertensive Emergency
A hypertensive emergency is the acute onset of severe hypertension in association with severe and rapidly worsening symptoms of end-organ damage (~1% of hypertensive patients). It usually occurs when diastolic pressure >120–130 mm Hg.
Clinical Presentation.
Neurologic: encephalopathy, headache, confusion, seizures, subarachnoid or intrace- rebral hemorrhage
Cardiac: chest pain, myocardial infarction, palpitations, dyspnea, pulmonary edema, jugular venous distension, gallops
Nephropathy: acutely progressive hematuria, proteinuria, renal dysfunction
Retinopathy: papilledema, hemorrhage, blurred vision
To diagnose, the lab evaluation will be the same as for essential hypertension, except there is no concern of artifactual “white coat hypertension” given the clear symptoms. CT scan of the head may be necessary to exclude hemorrhage. EKG is more important as an initial test to exclude infarction.
Treatment. IV therapy is indicated; nitroprusside and labetalol are the best agents. For those with evidence of myocardial ischemia, use nitroglycerin. Enalaprilat is an IV ACE inhibitor that is now being used as well. Other less commonly used agents include esmolol and nicardip- ine.
The most important point in management is not to lower the pressure too far (e.g., not
<95–100 mm Hg diastolic) so as not to compromise myocardial or cerebral perfusion. The initial goal is to reduce BP by no more than 25% within the first 1−2 hours.
Secondary hypertension is hypertension in the presence of an identifiable underlying cause (<5% cases of hypertension). Renal artery stenosis is the most common cause.
The following groups should be screened for secondary hypertension:
Those who become hypertensive either very young or very old (age <25 or >55)
Those with a key feature of history, physical examination, or laboratory abnormality consistent with a particular form as described below
Those who remain hypertensive despite increasing dosages and numbers of antihyper- tensive medications, i.e., those refractory to what should normally be effective therapy
Renal artery stenosis is caused by atherosclerotic disease in elderly persons and fibromuscu- lar dysplasia in young women. The key feature is an upper abdominal bruit radiating laterally (50–70% of patients). The best initial screening test is the renal artery duplex U/S.
The captopril renogram is a noninvasive way to confirm diagnosis; it measures the uptake of a radioisotope before and after the administration of captopril. A
positive test is when there is decreased uptake of the isotope (i.e., decreased GFR) after giving the captopril. Accuracy is diminished with renal insufficiency.
The arteriogram is still the best method for confirming the diagnosis.
Magnetic resonance angiography is also used to noninvasively detect stenosis.
Note
In resistant HTN, the BP is not able to be controlled in those who are adherent to full doses of a 3-drug regimen (including a diuretic).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
315
USMLE Step 2 l Internal Medicine
Treatment: The best initial treatment is percutaneous transluminal angioplasty.
If stenosis recurs, repeat the procedure.
If angioplasty fails, attempt surgical resection.
Reserve medical therapy with ACE inhibitors only for those in whom angioplasty or surgery fails or is not possible.
For unilateral disease it is not clear that angioplasty is superior to ACE inhibitors.
Primary hyperaldosteronism (Conn Syndrome) is caused by a unilateral adenoma (most common) (note that adenomas can also be bilateral) or by bilateral hyperplasia. Cancer is rarely the cause. The key features are hypertension in association with hypokalemia found on routine screening or symptoms of hypokalemia such as muscular weakness and polyuria and/ or polydipsia from a nephrogenic diabetes insipidus. Diagnose with elevated aldosterone in urine and blood. Treatment is surgical resection (for those with an adenoma) or potassium- sparing diuretics such as spironolactone (for those with hyperplasia).
Pheochromocytoma is most often due to a benign tumor of the adrenal gland; 10% are bilateral, 10% are malignant, and 10% are extra-adrenal. The key feature is episodic hypertension in associa- tion with headaches, sweating, palpitations, and tachycardia. Pallor or flushing may also occur. The best initial tests are urinary vanillylmandelic acid (VMA), metanephrines, and free urinary catecholamines. Plasma catecholamine evaluation is helpful as well. CT and MRI will localize the site of the tumor. Treatment is alpha-adrenergic blockade followed by surgical removal.
Cushing disease is most often due to ACTH hypersecretion by a pituitary adenoma. The key feature is hypertension in association with characteristic cushingoid manifestations such as truncal obesity, buffalo hump, menstrual abnormalities, striae and impaired healing, etc.
Dexamethasone suppression testing and 24-hour urine cortisol are the best initial tests. Treatment is surgical resection when possible.
In coarctation of the aorta, the key feature is hypertension markedly greater in the upper extremities compared with the lower extremities.
Miscellaneous. Other causes of secondary hypertension are the use of oral contraceptives, acromegaly, congenital adrenal enzyme deficiencies, and virtually any cause of chronic renal disease such as glomerulonephritis, polycystic disease, diabetic nephropathy, or chronic pyelonephritis.
Antihypertensive Medications
Diuretics
Antihypertensive medications can be divided into categories: thiazide diuretics (hydrochloro- thiazide, chlorthalidone, metolazone, and indapamide), loop diuretics (furosemide, bu- metanide, and torsemide), and potassium-sparing diuretics (spironolactone, amiloride, and triamterene).
Specific indications: CHF, edematous states, African-American patients; least expensive
Side effects: decrease potassium and magnesium; increase calcium, uric acid, glucose, LDL; gynecomastia
Relative contraindications include diabetes, gout, and hyperlipidemia.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
316
Chapter 8 ● Nephrology
ACE inhibitors
ACE inhibitors include benazepril, enalapril (IV only), captopril, enalapril, lisinopril. quinapril, and ramipril.
Specific indications: diabetics with hypertension to prevent neuropathy (with BP goal 130/80 mm Hg), CHF as afterload reduction, postmyocardial infarction with left ventricular impairment
Side effects: cough, angioneurotic edema, neutropenia, hyperkalemia, taste disturbances, and anaphylactoid reaction
Absolute contraindications include bilateral renal artery stenosis and pregnancy. Relative contraindications include less effectiveness in African-American patients.
Calcium channel blockers (CCBs) include amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, and verapamil.
Specific indications: angina pectoris, supraventricular arrhythmia, migraine, Raynaud phenomenon, esophageal spasm
Side effects: peripheral edema, constipation, heart block, reflex tachycardia
Relative contraindications include atrioventricular conduction defects, CHF from systolic dysfunction.
Angiotensin receptor antagonists
Angiotensive receptor antagonists include losartan, candesartan, valsartan, telmisartan, and irbesartan. This is the newest class of antihypertensives, with few side effects.
Specific indications: intolerance to ACE inhibitors (especially because of cough)
Absolute contraindications include pregnancy.
Beta blockers include acebutolol, atenolol (common), metoprolol (common), nadolol, pindolol, and timolol. Specific indications include myocardial infarction or ischemic heart disease; supraventricular arrhythmia; migraine headache, glaucoma, anxiety (resting tachycar- dia); and congestive failure from diastolic dysfunction. Side effects include bronchospasm, heart block, bradycardia, Raynaud phenomenon, depression, impotence, fatigue, decreased HDL, increased triglycerides, hyperglycemia. Relative contraindications include asthma or COPD, atrioventricular conduction defects, CHF from systolic dysfunction, diabetes because of masking signs of hypoglycemia.
Central-acting sympatholytics include clonidine, guanfacine, guanabenz, and methyldopa. Clonidine can be useful in opiate detoxification. Side effects include depression, fatigue, dry mouth, impotence, bradycardia, heart block, memory loss. Methyldopa gives hepatitis and Coombs-positive hemolytic anemia. Relative contraindications include elderly or depressed patients.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
317
USMLE Step 2 l Internal Medicine
Direct vasodilators include hydralazine and minoxidil. Hydralazine is used in eclampsia, while minoxidil is used topically to treat baldness. Side effects include a lupus-like syndrome (hydralazine) and marked fluid retention, pericardial effusion, and hirsutism (minoxidil).
Relative contraindications include angina pectoris.
Alpha-adrenergic blockers include doxazosin, prazosin, and terazosin, used for those with lipid disorders (they reduce LDL and increase HDL), prostatic hypertrophy (to reduce obstructive symptoms). Side effects include syncope after the first dose, dizziness, headache. There are no relative contraindications.
Practice Questions
What acid-base disorders are represented by the following sets of arterial blood tests?
– HCO3 , mEq/L | |||
For questions 2–5 use the following choices. Select the lab values that would be appropriate. An answer may be used once, more than once, or not at all.
A 60-year-old man with chronic bronchitis develops persistent diarrhea
A 56-year-old woman with chronic bronchitis is started on diuretic therapy for peripheral edema, resulting in a 3-kg weight loss
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
318
Chapter 8 ● Nephrology
Answers
1.
3
Metabolic acidosis (low pH, low HCO – concentration, compensatory reduction in
PCO2).
3
3
Respiratory alkalosis. Note that a low HCO – concentration does not necessarily imply a primary metabolic acidosis (high pH, low PCO2, compensatory reduction in HCO – concentration).
3
Combined respiratory and metabolic acidosis (low pH, high PCO2, low HCO –
concentration).
3
Metabolic alkalosis (high pH, high HCO – concentration, compensatory increase in
PCO2).
All the answer choices show respiratory (Pco2 >40 mm Hg) acidosis (pH <7.40). Normal Pco2 is 40 mm Hg and normal HCO– is 24 mEq/L.
A 60-year-old man with chronic bronchitis develops persistent diarrhea: The correct answer is (B) 7.22 pH, 60 mm Hg Pco2, 26 mEq/L HCO3-. Chronic bronchitis suggests chronic respiratory acidosis.
In chronic respiratory acidosis, HCO– increases 3.5 mEq/L for every 10 mm Hg increase in the Pco2.
The expected HCO– in choice A would be 24+(2.5*3.5) = 33 mEq/L.
The expected HCO– in choices B or C would be 24+(2*3.5) = 31 mEq/L.
Diarrhea suggests an acute metabolic acidosis. In a metabolic acidosis, we would expect the HCO– to be lower than we just predicted. Therefore, only choice B fits a chronic respiratory acidosis with acute metabolic acidosis.
A markedly obese 24-year-old man: The correct answer is (C) 7.35 pH, 60 mm Hg Pco2, 32 mEq/L HCO3-. Marked obesity suggests chronic hypercapnia and chronic respiratory acidosis.
In chronic respiratory acidosis, HCO- increases 3.5 mEq/L for every 10 mm Hg increase in the Pco2
The expected HCO– in choice A would be 24+(2.5*3.5) = 33 mEq/L.
The expected HCO– in choices B or C would be 24+(2*3.5) = 31 mEq/L. Therefore, only choice C fits an isolated chronic respiratory acidosis.
A 14-year old girl with a severe acute asthma attack: The correct answer is (B) 7.22 pH, 60 mm Hg PCO2, 26 mEq/L HCO3–.
Acute asthma suggests an acute respiratory acidosis.
In acute respiratory acidosis, HCO- increases 1.0 mQ/L for every 10 mm Hg increase in Pco2.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
319
USMLE Step 2 l Internal Medicine
The expected HCO- in choice A would be 26+(2.5*1.0) = 26.5 mEq/L.
The expected HCO- in choices B and C would be 26+(2.0*1.0) = 26 mEq/L. Therefore, only choice B fits an acute respiratory acidosis.
A 56-year-old woman with chronic bronchitis is started on diuretic therapy for periph- eral edema, resulting in a 3-kg weight loss: The correct answer is (A) 7.37 pH, 65 mm Hg Pco2, 37 mEq/L HCO3-.
Diuretic use suggests superimposed metabolic alkalosis on the basis of volume contraction. In metabolic alkalosis, HCO– concentration should be higher than predicted. Therefore, only choice A fits a chronic respiratory acidosis with acute metabolic alkalosis.
Note that choice B can represent either chronic respiratory acidosis with metabolic acidosis or acute respiratory acidosis in isolation. Choice C can represent either acute respiratory acidosis with metabolic acidosis or chronic respiratory acidosis in isolation.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
320
PCuhlampotenroTloitglye #9
Learning Objectives
Interpret results of pulmonary function testing and chest radiography
Describe the presentation and management of obstructive lung disease, atelectasis, interstitial lung disease, and acute respiratory distress syndrome
Outline the presentation, diagnosis, and management of sleep apnea
List the types of lung cancer and their epidemiologic associations and prognosis
Present risk factors, diagnosis, and treatment plan for pulmonary thromboembolism
DIAGNOSTIC TESTS
Pulmonary function tests (PFTs) are non-invasive tests used mainly to do the following:
Categorize types of lung process (restrictive versus obstructive)
Assess disease severity (in overall prognosis and preoperative evaluation)
Evaluate post-treatment lung function
Spirometry allows the determination of most lung volumes and capacities, as well as expiratory flows and bronchodilator response; it can be done in the office setting. Complete PFTs are done in the pulmonary lab and allow the measurement of TLC, DLCO, and methacholine challenge testing.
PFTs consist of different tests:
Static lung compartments are measured by lung volumes, such as total lung capacity (TLC), residual volume (RV) and vital capacity (VC).
Airflow or air movement is measured by the expiratory flow rate (ratio of forced expiratory volume in 1 second to forced vital capacity [FEV1/FVC] and forced expiratory flow 25−75% of expiration [FEF25–75, also called midmaximal flow rate MMFR]).
Clinical Pearl Perform PFTs in all patients before they undergo lung
resection surgery.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
321
USMLE Step 2 l Internal Medicine
Alveolar membrane permeability is measured by the diffusing capacity of a gas (DLCO).
The methacholine challenge test is an adjunct test used for evaluating bronchial hyperactivity in asthma patients who have normal PFTs.
Generally, <80% of predicted in any lung volume or flow rate is considered abnormal, while
>120% of predicted is consistent with air trapping.
Table 9-1. Pulmonary Function Tests
PFT | Normal Range |
TLC | 80–120% predicted |
RV | 75–120% |
TLC
Ventilatory function is measured under static conditions when determining lung volume, thus allowing for the diagnosis of restrictive lung disease.
IC: inspiratory capacity FRC: functional residual
capacity VT: tidal volume
VC
VT
FRC
R V
RV
Figure 9-1. Determination of Lung Volumes
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
322
Chapter 9 ● Pulmonology
Table 9-2. Pulmonary Indices
Index | Description |
Total lung capacity (TLC) | Volume of gas in the lungs after maximal inspiration |
Residual volume (RV) | Volume of gas remaining in the lungs after forced maximal expiration (unused space) |
Vital capacity (VC) | Volume of gas exhaled with maximal forced expiration TLC = RV + VC or VC = TLC – RV |
Forced expiratory volumes
Forced expiratory volumes (FEVs) measure air movement in and out of the lungs (airflow measurement under dynamic conditions). They can determine the degree of obstruction by comparing the forced volume expired at 1 second (FEV1) with the forced vital capacity
(FVC). An assessment is made by calculating the FEV1/FVC ratio.
In patients with no obstruction, the ratio is ≥0.80 (80% of predicted).
In patients with chronic obstructive disease (emphysema and chronic bronchitis) and asthma, it is decreased.
In patients with restrictive disease, FEVs are normal or elevated because there is no problem with airflow.
In patients with asthma, FEV1/FVC may be normal because they may have normal airflow (no bronchoconstriction) when asymptomatic. In other words, when they are not experiencing an acute asthma attack, values may be normal.
Forced expiratory flow (FEF25–75) is another way to express airflow; it can be measured during the FEVs. Generally, consider the FEF25–75 equivalent to the FEV1/FVC, but the FEF25–75 usually detects obstructive disease earlier.
FEV1
FVC
1
sec
6
5
4
3
2
1
0
1
sec
1
sec
FVC
1
FEV
6
5
4
3
2
1
0
6
5
4
3
2
1
0
Normal
FEV1
FVC
FEVs can be determined during spirometry or full PFTs.
Seconds Seconds Seconds
FEV1 = 4.0
FVC = 5.0
FEV1 = 1.3
FVC = 3.1
FEV1 = 2.8
FVC = 3.1
3 4
1 2
4
3
2
1
3 4
1 2
Figure 9-2. Forced Expiratory Volumes
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
323
USMLE Step 2 l Internal Medicine
Clinical Pearl
Patients with asthma may have normal PFTs. In these cases, methacholine challenge will provoke an asthmatic crisis and allow the diagnosis of asthma to be made by PFTs. Thus, perform methacholine challenge only for patients with normal PFTs and for whom you are considering a diagnosis of asthma.
Carbon monoxide diffusing capacity
Lung diffusion testing is used to determine how well oxygen passes from the alveolar space of the lungs into the blood. Whereas spirometry measures the mechanical properties of the lungs, the lung diffusing capacity test (DLCO) measures the ability of the lungs to perform gas exchange.
The single-breath DLCO test requires the patient to inhale DLCO gas consisting of helium, carbon monoxide, and room air. Generally, diffusing capacity is reduced when alveolar walls are destroyed and pulmonary capillaries are obliterated by emphysema, or when the alveolar-capil- lary membrane is thickened by edema, consolidation, or fibrosis (as in interstitial lung disease).
PFTs with an obstructive pattern and decreased DLCO should prompt the consideration of emphysema. PFTs with a restrictive pattern and decreased DLCO are likely to be some type of interstitial lung disease (intrapulmonary restriction) or mild left heart failure.
Increased DLCO may be seen in pulmonary hemorrhage, e.g., Goodpasture syndrome.
Inflammation and
formation of scar tissue
Interstitial Lung
Disease
Figure 9-3. Alveolar Diffusing Capacity
Methacholine challenge test
Bronchoprovocation with methacholine is done to evaluate patients with cough or wheezing and who have a normal PFT, for possible asthma (bronchial reactivity).
During the test, the patient inhales an aerosol of methacholine. Results of PFTs (e.g., spirom- etry) performed before and after the inhalations are used to quantitate the response. A positive test is defined as a decrease from the baseline FEV1 of 20% or more.
Bronchodilator reversibility
Nonreversible obstructive lung disease and reversible obstructive lung disease can be distin- guished by giving the patient an inhalation of a beta-agonist (albuterol). Consider asthma as the likely diagnosis when PFTs show evidence of an obstructive pattern, but then reverse by
>12% and 7,200 mL after using the bronchodilator.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
324
Chapter 9 ● Pulmonology
Flow Volume Loops
Flow volume loop diagrams also express airflow in different lung diseases and give the relationship between flow rates compared with lung volumes. On the y-axis is flow rate and on the x-axis is volume. Lung volumes increase to the left on the abscissa. The shape of the loop can characterize the type and distribution of airway obstruction.
When comparing a normal flow volume loop with one of restrictive lung disease, the restrictive lung disease alters the size of the loop (a shift to the right of the x-axis), which is related to a reduction in lung volumes.
On the other hand, obstructive lung disease alters the shape of the loop by causing a reduction of airflow (alterations on the y-axis).
In the case of a fixed airway-obstruction (tracheal stenosis after prolonged intubation), the flow volume loop is flattened on the top and bottom.
With dynamic extrathoracic airway obstruction (vocal cord paralysis), the obstruction occurs mostly with inspiration while expiration is mostly normal. This effect causes the flow volume loop to be flattened only on bottom.
0
Total
lung capacity
Figure 9-4. Flow Volume Loops
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
325
O
(Liters/sec)
Expiratory
flow
USMLE Step 2 l Internal Medicine
Clinical Pearl
FEO may occur in the setting of a tracheal tumor or foreign object aspiration or tracheal stenosis after prolonged intubation.
8
N
R
N: normal R: restrictive
O: obstructive
0
6
5
4
3
2
1 0
Volume
Inspiratory
flow
The most important factor in gas exchange is oxygen delivery (Do2) to the vital organs. Remember, Do2 is not Pao2 (Pao2 is calculated in the arterial blood gases). We can calculate Do2 from the following equation:
Do2 = Cardiac Output × (1.34 × Hb × HbSat) + 0.0031 + Pao2
where Do2 is oxygen delivery, HbSat is hemoglobin saturation, and Pao2 is partial pressure of oxygen in the blood (oxygen dissolved in plasma).
Do not memorize this formula, just know the concept.
Notice that the amount of oxygen delivered to the tissues accounted for by the Pao2 (oxygen dissolved in blood) is minimal. The most important factors in the delivery of oxygen to the vital organs are the cardiac output and hemoglobin.
In a critically ill patient, it is most important (the next step) to keep the hemoglobin and cardiac output near normal. There will be minimal change in Do2 if you increase the Pao2 from 60 to 100 mm Hg by giving the patient 100% oxygen.
The alveolar–arterial gradient (PAo2–Pao2 gradient) is useful in the assessment of oxygen- ation and is calculated by the following formula:
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
326
Chapter 9 ● Pulmonology
PAo2−Pao2 gradient = (150 − 1.25) × Pco2 − Pao2 or
A − a = [150 − (1.25 × PaCO2) − PaO2]
Know this formula and how to calculate the PAo2–Pao2 gradient.
The formula above is valid only in patients who are breathing room air. This gradient is 5–15 mm Hg in normal young patients. It increases with all causes of hypoxemia except hypoventi- lation and high altitude. The gradient also increases with age.
In the clinical setting, a patient who has overdosed from opiates (and has decreased respiratory rate) would have severe hypoxemia but a normal gradient.
CHEST RADIOGRAPHY
Chest radiography is often the initial diagnostic study performed to evaluate patients with respiratory symptoms. It may also be the initial evidence of pulmonary disease in a patient without symptoms, e.g., the pulmonary nodule found on an incidental x-ray.
Dr. Conrad Fischer
Figure 9-6. Bilateral Interstitial Infiltrates on Chest X-ray
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
327
USMLE Step 2 l Internal Medicine
Clinical Pearl
In all patients with a pulmonary nodule, first try to obtain an old chest x-ray.
Pulmonary Nodule
A 26-year-old man is found to have a 2.5-cm calcified nodule in the right middle lung on a routine chest x-ray before starting his residency. He has never smoked and otherwise feels well. The physical examination is unremarkable. What will you recommend for this patient?
The solitary pulmonary nodule that is found incidentally on an x-ray poses a specific problem for the clinician. Almost one-third of all solitary nodules are malignant.
Calcification of the nodule points toward a benign diagnosis, e.g., popcorn calcifications usually are caused by hamartomas, whereas bull’s-eye calcifications are caused by granulomas.
The first step is to look for a prior x-ray. Finding the same pulmonary nodule on an x-ray done years ago may save you from doing any further workup. If no prior x-ray is available, then consider whether this patient is high or low risk for lung cancer.
In low-risk patients, age <35 and nonsmokers with calcified nodules, follow the patient with chest x-ray or chest CT every 3 months for 2 years. Stop the follow-up if after 2 years there is no growth.
High-risk patients age >50 with a smoking history and a nodule are likely to have bronchogenic cancer. The best diagnostic procedure is to biopsy (or possibly resect) the nodule. Bronchoscopy will not reach peripheral lesions and will mislabel 10% of central cancers by finding only nonspecific inflammatory changes. Bronchoscopy is performed blindly and the specimen obtained can be limited, hence the nonspecific findings (inflammation, etc.). If you suspect cancer in a patient and the bronchos- copy returns with a negative result, open lung biopsy and lung nodule resection must be considered. For peripheral nodules, consider CT-guided biopsy, VATS, or open lung biopsy and nodule removal. PET-CT has not so far been well studied in the evaluation of high-risk patients with lung nodules.
A 67-year-old man presents with complaints of dyspnea and pleuritic chest pain that has worsened over the past month. He has also noticed weight loss of 20 pounds and low-grade fever over this time period. On physical examination his respiratory rate is 24/min, and you find decreased air entry in the right lower lobe with dullness to percussion. Chest x-ray shows a pleural effusion involving about one-third of the lung field. A decubitus x-ray shows layering of the fluid.
Definition. The accumulation of fluid in the pleural cavity. It is either transudative or exudative.
Transudative effusion is caused by systemic factors: either increased hydrostatic pressure (e.g., CHF) or decreased oncotic pressure (e.g., nephrotic syndrome or cirrhosis). Because these diseases are systemic, they usually cause bilateral and equal effusion.
A transudative effusion needs no further evaluation. It resolves by adequate treatment of the primary disease.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
328
Chapter 9 ● Pulmonology
Exudative effusion is caused by local processes: pneumonia, cancer, and tuberculosis.
An exudative effusion will cause unilateral effusions. This type of effusion needs further investigation.
How do we make the distinction between these two?
Thoracentesis should be performed for new and unexplained pleural effusion when sufficient fluid is present to allow a safe procedure. It is reasonable to observe pleural effusion when there is overt CHF (especially if bilateral), viral pleurisy, or recent thoracic or abdominal surgery. However, it is important not to assume that new effusions in a patient with a history of CHF are solely due to the CHF. Have a low threshold for performing diagnostic thoracentesis in any new or unexplained effusions.
Table 9-3. Causes of Pleural Effusion
Transudative | |
Heart failure | |
Liver disease | |
Atelectasis | Collagen vascular disease (rheumatoid arthritis, systemic lupus erythematosus) |
Get 2 tests from the thoracocentesis fluid—lactate dehydrogenase (LDH) and protein—and get 2 tests from the serum—LDH and protein. Do the ratios of effusion to serum for these measurements, and you have a diagnosis.
Table 9-4. Light Criteria for Exudative Pleural Effusion
Transudative | Exudative | |
LDH effusion | <200 IU/mL | >200 IU/mL |
LDH effusion/serum ratio | <0.6 | >0.6 |
Protein effusion/serum ratio | <0.5 | >0.5 |
If at least 1 criterion is not met, then this is an exudative effusion; in that case, further evalua- tion has to be done.
One of the few conditions that can cause a transudate or exudate is pulmonary embolism (PE). The clinical significance of this is that if a patient has a transudative effusion but no apparent cause, consider PE.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
329
USMLE Step 2 l Internal Medicine
Parapneumonic effusion is caused by bacterial pneumonia. A thoracocentesis is mandatory also in this setting to rule out a complicated parapneumonic effusion (because of the possibility of progression to an empyema). An empyema (or complicated effusion) needs chest-tube drainage to resolve, while an uncomplicated parapneumonic effusion responds to antibiotics alone.
The most common causes of malignant pleural effusion are lung cancer, breast cancer, and lymphoma. When considering a malignant pleural effusion, make sure to send the thoracocen- tesis fluid for cytologic examination.
Hemorrhagic pleural effusion may be seen in mesothelioma, metastatic lung or breast cancer, pulmonary thromboembolism (with infarction), and trauma.
In patients with lymphocytic predominant exudative pleural effusions, consider tuberculosis. The pleural effusion is thought to be due to a hypersensitivity reaction to the tuberculosis mycobacterium and its antigens. The adenosine deaminase is elevated, and the polymerase chain reaction (PCR) for tuberculous DNA is positive. The acid-fast stain and culture for tuberculosis are positive in <30% of the cases. A pleural biopsy confirms the diagnosis and is the most sensitive and specific test for pleural tuberculosis.
Always perform thoracocentesis under the guidance of ultrasonography. If ultrasonography is not available, then perform a decubitus chest x-ray before the thoracocentesis. If the decubitus chest x-ray detects 1 cm or more of free-flowing fluid, the thoracocentesis can be performed with a minimal risk of complications. If the decubitus detects non-free fluid (loculated), it would be safer to perform an U/S-guided thoracocentesis.
Wikipedia, James Heilman, MD
Figure 9-7. Pleural Effusion
Evaluating patients with acute respiratory compromise and distress
Respiratory compromise may result from airway obstruction (asthma, COPD, foreign object), but it also accompanies parenchymal lung disease (bacterial or viral pneumonia, lung injury), heart failure, pulmonary embolism, neurogenic processes (respiratory depression from opiates), and neuromuscular disease (myasthenia gravis).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
330
Chapter 9 ● Pulmonology
Respiratory distress is usually the presenting complaint or sign. Complaints of shortness of breath or signs of tachypnea or labored breathing are the most common. The patient may also develop neurologic symptoms: agitation, confusion, and a depressed level of consciousness. Stridor indicates upper airway obstruction.
The physician’s first task is to ensure that the patient’s airway is patent and that breathing is adequate. Supplemental oxygen should be provided immediately to ensure adequate oxygen saturation. The resources to perform endotracheal intubation and assisted ventilation should be made available.
The history should focus on the quickness of onset, as well as associated symptoms (cough, fever, etc.). Acute presentations accompanied by cough, fever, and sputum production suggest an infectious etiology. Sudden onset of dyspnea without systemic symptoms should raise the possibility of airway obstruction, cardiac disease, or thromboembolic disease. Chronic and progressive dyspnea (with or without recent exacerbation) is usually associated with a chronic pulmonary process, like interstitial lung disease or COPD.
The physical examination should focus on finding the cause, as well as assessing the degree of respiratory compromise. A respiratory rate >30/min in an adult suggests severe respiratory compromise. Wheezing on auscultation accompanies asthma and COPD. Localized wheezing usually suggests a foreign object or mass. Rales on examination may accompany pneumonia, interstitial lung disease, or heart failure. Consolidative changes may accompany pneumonia or atelectasis. Normal lung examination may be seen in thromboembolic disease, infections like Pneumocystis carinii, and disorders of the central respiratory drive.
The hallmark of acute respiratory failure is a rise in PCO2 accompanied by a drop in pH. The bicarbonate level will initially be normal, but will increase over 24–48 hours with the appropri- ate renal compensation. Hypercapnia may accompany hypoxemia or may be absent if ventila-
tion is adequate. The presence of metabolic acidosis (lactic acidosis) in the presence of hypercapnia should prompt the consideration of mechanical ventilation.
In the setting of acute-on-chronic respiratory failure, the administration of supplemental oxygen is often associated with a rise in PaCO2. Although attributed to a decreased respiratory drive, the pathophysiology of this is more complex. For the clinician, fear of a rising PaCO2 should never preclude the administration of enough supplemental oxygen to ensure adequate oxygen delivery. The target range of 88–92% oxygen saturation usually allows for adequate oxygen delivery while minimizing the potential increase in PaCO2.
Other diagnostic tests
B-type natriuretic peptide (BNP) appears useful as an adjunct to clinical assessment in determining the cause of acute dyspnea in patients presenting emergently. An elevated BNP is seen in almost all patients with left heart failure. It is important to remember that cor pulmonale and acute right ventricular failure (thromboembolism) may also cause a rise in the BNP. Thus, although the BNP is a very sensitive test for heart failure, it is not specific.
The chest x-ray is particularly helpful in determining the cause of respiratory failure. A chest x-ray without parenchymal infiltrates accompanies respiratory failure due to thromboembolism, central respiratory depression, neuromuscular disease, and upper airway obstruction. Airway obstruction that accompanies asthma and COPD is usually
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
331
USMLE Step 2 l Internal Medicine
associated with evidence of hyperinflation (large lung volumes and hyperlucency). The chest x-ray is diagnostic in cases of respiratory compromise caused by large pleural effusions or tension pneumothorax. Focal infiltrates suggest bacterial, viral, or fungal pneumonia; aspiration; or pulmonary hemorrhage. Unusual causes of localized infil- trates may be Churg-Strauss or Wegener granulomatosis. Heart failure and ARDS present with a diffuse edema pattern.
Treatment. New, persistent hypoxemia is generally an indication for admission to the hospital. The need for mechanical ventilation and close monitoring of a patient with respiratory compro- mise is an indication for admission to the ICU. Also, ICU admission should be considered for all patients with increasing oxygen demands, as well as those requiring continuous nursing.
The presence of respiratory acidosis and hypercapnia in a patient presenting with asthma exacerbation is an ominous sign and should prompt consideration for intubation and mechanical ventilation. Indications for intubation (with or without ventilation) also include upper-airway injury (burns, laryngeal edema, trauma) and airway compromise, often in the setting of neurologic depression with loss of protective reflexes, including gag and cough.
ARDS is a frequent cause of respiratory failure in patients suffering from other serious illnesses. ARDS represents a diffuse inflammatory response of the lung and develops within 24–72 hours of the onset of illness or injury. The clinical presentation is increasing respiratory distress with tachypnea and hypoxemia. The chest x-ray reveals diffuse pulmonary infiltrates, consistent with pulmonary edema (noncardiogenic pulmonary edema).
Which of the following does not present with an exudative pleural effusion?
Lung cancer
Liver disease
Pancreatitis
Pneumonia
Tuberculosis
Answer: B
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
332
Chapter 9 ● Pulmonology
VENTILATION
Noninvasive Ventilation
Noninvasive ventilation (NIV) is a modality that supports breathing without the need for intubation. NIV avoids the adverse effects of invasive ventilation and has become an important mechanism of ventilator support both inside and outside the ICU.
Forms of NIV include bilevel positive airway pressure (BiPAP) and continuous positive air- way pressure (CPAP).
Bi-level positive airway pressure (BiPAP or BPAP) applies 2 different levels of PAP, i.e., it delivers positive pressure at alternating levels—higher for inspiration and lower for expiration— optimizing lung efficiency and at the same time diminishing the work of breathing. BPAP has been shown to be an effective management tool for COPD and acute (pneumonia, status asthmaticus, etc.) and chronic respiratory failure.
Continuous positive airway pressure (CPAP) applies air pressure on a continuous basis, allowing the airways to continuously be open (splinted). It is typically used in the treatment of obstructive sleep apnea, preterm infants with underdeveloped lungs, CHF with pulmonary edema, near drowning, and other severe causes of respiratory distress. Portable CPAP machines used at home deliver a constant flow of pressure and are thus effective at preventing the airway from collapsing.
Invasive Ventilation
Invasive ventilation, or mechanical ventilation, follows endotracheal intubation, and is used to improve oxygen exchange during acute hypoxemic or hypercapnic respiratory failure with respiratory acidosis. While hypoxemia and respiratory failure is one of the common reasons for endotracheal intubation, it is also introduced in order to protect the airways.
Positive end-expiratory pressure (PEEP) is the alveolar pressure above atmospheric pressure that exists at the end of expiration.
Applied (extrinsic) PEEP is one of the first ventilator settings chosen when mechani- cal ventilation is initiated, and it is set directly on the ventilator.
A small amount of applied PEEP (4−5 cm H2O) is used in most mechanically venti- lated patients to mitigate end-expiratory alveolar collapse. A higher level
(>5 cm H2O) is sometimes used to improve hypoxemia or reduce ventilator-associated lung injury in patients with acute respiratory distress syndrome or another type of hypoxemic respiratory failure.
Complications of PEEP include decrease in systemic venous return, pulmonary barotrauma, renal dysfunction, and electrolyte imbalance.
Note
Don’t confuse BiPAP with CPAP, which applies a single level of positive airway pressure throughout the whole respiratory cycle and is used for clinical conditions such as obstructive sleep apnea.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
333
USMLE Step 2 l Internal Medicine
Figure 9-8. Effect of PEEP (Positive End-Expiratory Pressure)
Both PEEP and CPAP stent the alveoli open and thus recruit more of the lung’s surface area for ventilation. But while PEEP imposes positive pressure only at the end of the exhalation, CPAP devices apply continuous positive airway pressure throughout the breathing cycle. Thus, no additional pressure above the level of CPAP is provided, and patients must initiate all of their breaths.
A 26-year-old woman with a history of asthma presents to the emergency room with 3 days of progressive wheezing and shortness of breath after an upper respiratory tract infection. She is taking inhaled albuterol and an over-the-counter medication for her cold symptoms. Her respiratory rate is 28/min and pulse 110/min; she is afebrile. Her right nasal turbinate is edematous and erythematous. There is evidence of wheezing throughout both lungs, but no crackles are noted. Supplemental oxygen by nasal cannula is administered. What should be the next appropriate treatment?
334
Asthma is a disease characterized by inflammatory hyperreactivity of the respiratory tree to various stimuli, resulting in reversible airway obstruction. A combination of mucosal inflammation, bronchial musculature constriction, and excessive secretion of viscous
mucus-causing mucous plugs will produce bronchial obstruction. The bronchial hyperreactiv- ity occurs in an episodic pattern with interspersed normal airway tone.
Asthma can occur at any age but is usually seen in young persons, 50% of whom “outgrow” their asthma by adulthood.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
Chapter 9 ● Pulmonology
There are 2 types of asthma. Many patients have features of both types.
Intrinsic or idiosyncratic asthma (50% of asthmatics who are nonatopic [nonallergic]). A bronchial reaction occurs secondary to nonimmunologic stimuli, such as infection, irritating inhalant, cold air, exercise, and emotional upset. The asthma attacks are severe, and prognosis is less favorable.
Extrinsic (allergic, atopic) asthma (20% of asthmatics) results from sensitization. Specific immunoglobulins (IgE class [type 1]) are produced, and total serum IgE concentration is elevated. There is a positive family history of allergic disease. Extrin- sic asthma is precipitated by allergens. Other symptoms include allergic rhinitis, urticaria, and eczema. Prognosis is good.
Respiratory infections are the most common stimuli to cause asthma exacerbation; studies have documented that viruses (respiratory syncytial virus in young children, rhinoviruses in adults) are the major causes.
Pharmacologic stimuli are very important in some cases; the most common etiologic agents associated with asthma exacerbation are aspirin, coloring agents such as tartrazine, and
β-adrenergic antagonists.
The typical aspirin sensitivity (10% prevalence) nasal polyposis syndrome, affecting adults, starts with perennial vasomotor rhinitis; later, asthma occurs with minimal ingestion of aspirin.
There is significant cross-reactivity between aspirin and other NSAIDs. Patients can be desensitized by daily administration of aspirin; cross-tolerance also develops to other NSAIDs.
The mechanism by which aspirin and similar drugs cause asthma appears to be chronic over-excretion of leukotrienes, which activate the mast cells. This is the reason why leukotriene inhibitors are considered to be so effective.
Pathophysiology. There is a narrowing of large and small airways caused by hypertrophy and spasm of bronchial smooth muscle, edema and inflammation of the bronchial mucosa, and production of viscous mucus. The mediators released by the lung during an acute asthmatic attack are histamine, bradykinin, leukotrienes (LTs) C, D, and E, and prostaglandins (PGs) E2,
F2α, and D2, which cause an intense inflammatory process leading to bronchoconstriction and
vascular congestion. The cells thought to play an important role in the inflammatory response
are the mast cells, lymphocytes, and eosinophils.
Signs and Symptoms. In a mild attack, slight tachypnea, tachycardia (increased respiratory rate), prolonged expirations, and mild, diffuse wheezing are seen. In a severe attack, use of accessory muscles of respiration, diminished breath sounds, loud wheezing, hyper-resonance (increased vocal fremitus), and intercostal retraction are noted.
Poor prognostic factors include fatigue, diaphoresis, pulsus paradoxus (>20 mm Hg), inaudible breath sounds, decreased wheezing, cyanosis, and bradycardia.
Variants of asthma include asthma presenting primarily with nocturnal cough and exercise- induced asthma (both presentations of asthma are commonly tested).
In the acute phase, arterial blood gas (ABG) abnormalities will be consistent with a decrease in arterial carbon dioxide tension (PaCO2), increase in pH, and normal or low Pao2. In severe asthma or status asthmaticus there will be a decreased Pao2, increased PaCO2, and decreased pH (bicarbonate level usually will not be elevated in an acute setting, but it becomes elevated
Clinical Pearl
Samter’s triad or aspirin- sensitive asthma:
Asthma
Nasal polyposis (causing
recurrent sinus disease)
Sensitivity to aspirin and NSAIDs
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
335
USMLE Step 2 l Internal Medicine
in chronic obstructive pulmonary disease). A normal PaCO2 may indicate respiratory muscle fatigue in an acute asthmatic patient.
Chest x-ray findings are nonspecific in an asthmatic attack. The chest x-ray may be helpful in ruling out acute infection as the cause of an acute attack.
Diagnosis. PFTs show an obstructive pattern that typically reverses with bronchodilation (FEV1 must show 12% and 200 mL reversibility at 5 and 20 min with the use of a β2-adrenergic agonist). Sometimes the PFTs may be entirely normal because asthma is reversible and
episodic; in this case a provocative challenge may be performed with methacholine or cold air, which typically shows a decrease in FEV1/FVC or FEF25–75 of 20%.
Treatment. β-adrenergic agonist inhalers like albuterol (salbutamol) and terbutaline are the mainstay of treatment in acute and chronic asthma. Inhaled (metered-dose inhalers [MDIs]) β-adrenergic agonists are the preferred route of administration because they allow maximal bronchodilation with minimal side effects. Their most common side effect is tremor.
β-adrenergic agonists alone terminate approximately 70% of asthmatic attacks.
Salmeterol is a long-lasting (12 h) type of albuterol that is effective in nocturnal cough variant and exercise-induced asthma. Salmeterol has no benefit in acute episodes.
β-adrenergic agonists must be used with caution in patients who have coexisting cardiovascular disorders, hypothyroidism, diabetes mellitus, hypertension, and coronary insufficiency.
Other adrenergic stimulant drugs like the catecholamines (isoproterenol, epinephrine, and isoetharine) are given orally or intravenously and are not routinely used.
Aminophylline (ethylenediamine salt of theophylline) and theophylline are only modest bron- chodilators. They are sometimes of benefit in chronic management, especially in patients with nocturnal cough. Their mechanism of action is by improving contractility of the diaphragm as well as other respiratory muscles. Generally, aminophylline and theophylline are not routinely used in asthma because they appear to add no benefit to optimal inhaled beta-agonist therapy.
Anticholinergic drugs (ipratropium bromide and tiotropium) have particular benefit in patients with heart disease, in whom the use of β-adrenergic agonists and theophylline may be danger- ous. Their major disadvantages are that they take significant time to achieve maximal broncho- dilation (~90 min) and they are only of medium potency.
Supplemental oxygen, by nasal cannula or mask, should be given immediately when a patient presents with acute asthma exacerbation. Always maintain an oxygen saturation above 90%.
The use of “routine” antibiotic treatment in asthma exacerbation has not been established. Two recent prospective trials have not showed a benefit. Antibiotic treatment should be considered in patients with symptoms (purulent sputum) and chest x-ray findings (infiltrates) consistent with bacterial pneumonia.
Treatment of asthma in the outpatient setting (chronic management) consists of looking for and removing environmental irritants and allergens. The goal is to remove or minimize contact with precipitating factors of asthma (such as pets).
Inhaled corticosteroids are the cornerstone of chronic asthma therapy in adults. They work by reducing airway inflammation. Inhaled corticosteroids have been shown in studies to reduce asthma exacerbations and hospitalizations. Side effects of inhaled corticosteroids include oral candidiasis, glaucoma, cataracts, diabetes, muscle weakness, and osteoporosis. Appropriate
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
336
Chapter 9 ● Pulmonology
technique in use of inhalers should be reviewed with the patient, as well as the use of spacers and/or mouth-rinsing to avoid oral candidiasis.
Systemic steroids are used only in acute exacerbations (for 10–14 days) and in the treatment of chronic severe asthma. Systemic corticosteroids should not be used before inhaled cortico- steroids.
Inhaled short-acting beta 2 agonists such as albuterol are the mainstays of treatment of chronic asthma and are usually used in conjunction with inhaled corticosteroids. Use of short-acting beta-2 agonists for 3 days/week indicates poor control of symptoms, and treat- ment should be intensified.
Inhaled long-acting beta 2 agonists like salmeterol and formoterol have a sustained effect on bronchial smooth muscle relaxation. They are indicated for the treatment of moderate to severe persistent asthma (after initial therapy with short-acting beta 2 agonist plus inhaled corticoste- roids), especially with a significant nocturnal component. A few things to note:
Not for use during acute exacerbation of asthma
Not for use alone; always use in conjunction with inhaled corticosteroids (studies show increased mortality when long-acting beta 2 agonists are used as a single agent)
The leukotriene modifiers inhibit 5-lipoxygenase, the enzyme involved in leukotriene produc- tion (LTC4, LTD4, LTE4), or competitive antagonist the principal moiety (LTD4). They are approved for severe asthma resistant to maximum doses of inhaled corticosteroids and as a last resort before using chronic systemic corticosteroids. Zileuton is a typical leukotriene inhibitor that is available. The receptor antagonists are zafirlukast and montelukast.
MAST cell stabilizers (cromolyn and nedocromil) have been used in the treatment of chronic asthma. In terms of preventing asthma exacerbations and reducing inflammation in adults, they are not as effective as inhaled corticosteroids. They may be used also in exercise-induced asthma and allergic asthma. Cromolyn and Nedocromil are used extensively in the chronic treatment of pediatric asthma.
Clinical guidelines have classified asthma in 4 categories, based on frequency, severity of symptoms, and requirements for medication. This classification provides general guidelines for therapy.
Mild intermittent
Mild persistent
Moderate
Severe
Treatment of asthma in the inpatient setting (acute exacerbation) requires a different approach. Referring to the case presented earlier, the patient is likely having an acute exacer- bation of asthma.
The treatment of choice is bronchodilator (albuterol); systemic corticosteroids (usually start IV), and oxygen. (Long-acting bronchodilators are contraindicated in the acute setting.)
Bad prognostic indicators in this patient would be cyanosis, silent lung, increased CO2. An ABG of 7.32/45/60 (with CO2 of 45) would be considered ominous.
Note
Neither short-acting nor long- acting beta 2 agonists address the inflammatory component of asthma.
Note
Theophylline is generally not preferred for the treatment of asthma.
For chronic asthma, use only as a possible adjunct to inhaled corticosteroids for difficult-to-control asthma.
For an acute exacerbation of asthma, a long-acting beta agonist plus inhaled corticosteroids is more effective.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
337
USMLE Step 2 l Internal Medicine
Note
Respiratory acidosis or ’normalization’ of pH in patients with acute asthma exacerbation may be an indication for intubation.
If, 3 days after hospitalization the patient is improving and you decide to send her home, her drug regimen would likely be oral prednisone taper, albuterol inhaler, steroid inhaler.
Suppose the patient returns 3 months later for follow-up. She needs documentation of asthma for her work. You would do a PFT to document the asthma, and confirm that her basic asthma regimen should be inhaled steroids daily and albuterol inhaler as needed.
For testing purposes, the guidelines are simplified into the following classifications.
Mild Intermittent Asthma
Symptoms of cough, wheeze, chest tightness, or difficulty breathing <2x/week
Flare-ups-brief, but intensity may vary
Nighttime symptoms <2x/month
No symptoms between flare-ups
Lung function test FEV1 that is ≥80 percent of normal values
Symptoms of cough, wheeze, chest tightness, or difficulty breathing daily
Lung function test FEV1 that is >60 percent but <80 percent of normal values
Severe Persistent Asthma
Symptoms of cough, wheeze, chest tightness or difficulty breathing continually
Nighttime symptoms frequently
Lung function test FEV1 that is ≤60 percent of normal values
Treatment: inhaled corticosteroid, SABA (as needed), leukotriene inhibitor, and LABA will likely be needed, as well as oral steroids (prednisone) at lowest possible dose
Do not stop leukotriene inhibitors and LABA once oral corticosteroids have been started
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
338
Chapter 9 ● Pulmonology
Allergic Bronchopulmonary Aspergillosis
Allergic bronchopulmonary aspergillosis (ABPA) is an allergic lung reaction to a fungus (most commonly Aspergillus fumigatus) seen in some patients with asthma or cystic fibrosis. Other fungi, including Penicillium and Candida, can cause an identical illness. In some peo- ple, the effects of the allergic reaction combine with the effects of the fungus to damage the airways and lungs further.
The fungus does not actually invade the lung tissue and directly destroy it; rather, it colonizes the mucus in the airways of patients with asthma or cystic fibrosis (both of whom have increased amounts of mucus) and causes recurrent allergic inflammation in the lung.
The alveoli become packed primarily with eosinophils.
If the disease has caused extensive damage, bronchiectasis and scarring occur.
The first indications of allergic bronchopulmonary aspergillosis are usually progressive symptoms of asthma, such as wheezing and shortness of breath, and mild fever. The person usually does not feel well. Appetite may decrease. Brownish flecks or plugs may appear in coughed-up sputum. Repeated chest x-rays show areas that look like pneumonia, but they appear to persist or migrate to new areas of the lung (most often the upper parts). In people with long-standing disease, chest x-ray or CT may show bronchiectasis.
The fungus itself, along with excess eosinophils, may be seen when a sputum sample is examined under a microscope. Blood test reveals high levels of eosinophils and antibodies to Aspergillus. The level of immunoglobulin E in the blood is also elevated. Skin testing can determine if the person is allergic to Aspergillus, though it does not distinguish between allergic bronchopulmonary aspergil- losis and a simple allergy to Aspergillus. Treatment is with corticosteroids.
Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD) includes patients with emphysema and chronic bronchitis. Emphysema and bronchitis must be identified as separate entities, but most patients with COPD have characteristics of both conditions.
Patients with chronic bronchitis have productive cough for most days of a 3-month period for at least 2 consecutive years.
Patients with emphysema have abnormal permanent dilation of air spaces distal to the terminal bronchioles with destruction of air space walls.
Both of these processes are defined by nonreversible obstruction of the airways. This is the pathognomonic differentiating finding on PFTs when compared with asthma.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
339
USMLE Step 2 l Internal Medicine
Cigarette smoking is a cause of COPD, with 10–15% of smokers developing COPD (80–90% of COPD patients are cigarette smokers). COPD symptoms usually begin after at least 20 pack-years of tobacco exposure. The number of pack-years of smoking correlates to
the reduction of FEV1. The fact that a small percentage (10–15%) of smokers develops COPD suggests that other factors may be involved in the pathogenesis. Air pollution, airway infec- tions, and allergies can lead to bronchitis.
α1-antitrypsin deficiency is a rare hereditary autosomal recessive disease that can cause emphysema and liver abnormalities.
Pathogenesis. After long-term exposure to cigarette smoke, inflammatory cells are recruited in the lung. These inflammatory cells in turn secrete proteinases, which may lead to air space destruction and permanent enlargement. Eventually, decreased elastic recoil (mainly in emphysema) and increased airway resistance (mainly with chronic bronchitis) occur.
Physical Examination. In emphysema, distant breath sounds will be heard on auscultation. In chronic bronchitis, there may be evidence of rhonchi and wheezes to auscultation. Signs and symptoms of right heart failure (cor pulmonale) and clubbing can also be seen on physical examination in COPD.
Figure 9-9. Clubbing of the Fingers Seen with Chronic Hypoxemia
In chronic bronchitis, increased pulmonary markings can be seen on chest x-ray; in emphy- sema, hyperinflation of bilateral lung fields with diaphragm flattening, small heart size, and increase in retrosternal space can be seen.
Cor pulmonale in COPD is associated with chronic pulmonary hypertension.
Diagnosis. PFTs are the diagnostic test of choice. On PFT, a reduction in FEV1/FVC ratio and FEF25–75 occurs. RV and TLC are usually increased in COPD. Emphysema will have a decreased DLCO, whereas chronic bronchitis will generally have a normal DLCO.
After a bronchodilator is given, you would expect the FEV1/FVC to remain the same or improve minimally.
Complications. Hypoxemia with nocturnal desaturation is sometimes seen. Secondary erythro- cytosis can result from chronically low Po2. Pulmonary hypertension is a complication that can lead to cor pulmonale and subsequent right heart failure. Chronic ventilatory failure and CO2 retention are seen in chronic bronchitis early and at the end stages of emphysema.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
340
Chapter 9 ● Pulmonology
Management of Stable Phase COPD. The goal in treatment is to treat airway inflammation and bronchospasm, reduce a• irway resistance and work of breathing, and improve gas exchange
and ventilation-perfusion (V/Q) mismatching.
Anticholinergic agents (ipratropium bromide [Atrovent®] and tiotropium) are the first-line drugs in COPD. These agents are given via MDI and control airway caliber and tone. Anticho- linergic agents can be used synergistically with β2-adrenergic agonists in patients with COPD.
β2-adrenergic agonists (albuterol) are used after anticholinergic agents. The inhaled route is the preferred administration.
Beta agonists are not first-line agents in the management of COPD because many of the patients have underlying heart disease and the tachycardia commonly associated with these agents may precipitate heart failure.
Chronic inhaled corticosteroids are reserved for severe cases of COPD.
Theophylline, a xanthine derivative, may be added to the regimen if beta-2 agonists and anticholinergics are not effective in managing the symptoms of chronic obstructive lung disease. Remember that theophylline has significant toxicity. Symptoms include nausea and vomiting, palpitations, and tremulousness. Death can occur from theophylline toxicity from cardiac arrhythmias.
The list of drug interactions with theophylline is significant. Theophylline levels increase with fluoroquinolones, clarithromycin, H2-blockers (cimetidine, ranitidine), certain beta blockers and calcium channel blockers. Theophylline levels decrease (due to increased clearance) with rifampin, phenytoin, phenobarbital, and smoking.
Despite the above treatments, the only interventions which have been shown to decrease mortality in patients with COPD are home oxygen and smoking cessation.
Home oxygen therapy is given to patients with hypoxemia (Pao2 <55 mm Hg or saturation
<88%), and the goal is to try to keep the O2 saturation >90% as much as possible, especially at night when patients generally desaturate. Patients with cor pulmonale will benefit from home
oxygen when Pao2 <59 mm Hg. A special category is the patient who desaturates with exercise; in that case, intermittent oxygen will be beneficial.
All patients with COPD must have the pneumococcal vaccine (Pneumovax®) every 5 years and the influenza vaccine yearly. They should also receive the H. influenzae vaccine if they were not previously immunized.
Several trials have failed to find a beneficial effect for the regular chronic use of inhaled corticosteroids in patients with COPD.
Management and Treatment of COPD Exacerbation (Acute Setting Treatment). Acute exacerbation of COPD is considered acute worsening of the patient’s respiratory symptoms (increased dyspnea, increased sputum volume, production of purulent sputum) that necessi- tates a change in medications.
The most common causes of COPD exacerbation are viral lung infections. Other precipitating causes that should be sought out are bacterial infections, heart failure, myocardial ischemia, pulmonary embolism, lung cancer, esophageal reflux disease, and medications (e.g., beta-blockers).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
341
USMLE Step 2 l Internal Medicine
Initial Management
Measure O2 saturation via pulse oximetry (on the spot) to determine oxygen saturation.
ABG determination is very useful to identify the level of hypercapnia and thus the severity of exacerbation.
Chest x-ray is expected in all patients with COPD exacerbation to identify pulmo- nary infiltrates consistent with pneumonia. It may also show evidence of pulmo- nary edema, indicating possible heart failure as the cause of the exacerbation.
Spirometry (and other PFT evaluation) is not helpful in COPD exacerbation because measurements (FEV1, etc.) have not been shown to correlate well with the severity of the exacerbation.
In the acute setting, check levels in patients on chronic treatment with theophyl- line. Drugs like erythromycin, cimetidine, and ciprofloxacin may decrease theophylline clearance and cause theophylline toxicity.
Other tests as part of the initial evaluation of COPD exacerbation might include CBC (looking for elevated WBCs and polycythemia); ECG (looking for new arrhythmias, e.g., atrial fibrillation that may precipitate heart failure and exacerbate COPD).
Any significant changes of hypercapnia or hypoxemia from baseline should prompt consideration for admission to the hospital. Also, patients on home O2 who have exacerbation, and those with severe symptoms, should be hospitalized.
Consider intubation and mechanical ventilation in patients with decreased levels of consciousness, cyanosis, or hemodynamic instability and in those with persistent hypoxemia despite adequate oxygen supplementation.
Oxygen supplementation should be titrated to ~90% saturation on the pulse oximeter. The first and foremost concern is to deliver adequate oxygenation. In COPD exacerbation, we should be concerned about CO2 retention as a secondary
Inhaled bronchodilators are the most effective medications to improve airway diameter (the drugs of choice). In acute COPD exacerbations, use both beta- agonists (albuterol) and anticholinergics (ipratropium) simultaneously. Trials have shown that administration of these drugs by a nebulizer or metered dose inhaler (MDI) with a spacer is equally efficacious. Patients with severe exacerba- tions are unable to hold their breath for more than a few seconds and are thus initially treated with nebulizers and then switched to the MDIs.
Systemic corticosteroids have now been shown in multiple trials to shorten the recovery time of lung function and decrease the length of stay in patients with COPD exacerbation. Corticosteroids may be given intravenously or orally because the efficacy is similar in both modes of administration. The equivalent of 60 mg prednisone appears to be the sufficient starting dose and is usually continued for 2 weeks. It makes sense clinically to start patients who have a severe exacerbation with IV methylprednisolone (it is difficult for these patients
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
342
Chapter 9 ● Pulmonology
to take oral meds), then change to oral prednisone as they improve. Inhaled corticosteroids have not been shown to improve outcomes in patients with COPD exacerbation and cannot be substituted for systemic corticosteroids.
Antibiotics seem to be beneficial in COPD exacerbations despite “normal” chest radiograms. Patients with productive, purulent cough benefit the most because they are more likely to have an underlying bacterial infection. Antibiotics commonly used are second-generation macrolides (clarithromycin, azithromy- cin), extended-spectrum fluoroquinolones (levofloxacin, moxifloxacin), cephalo- sporins (second- and third-generation), and amoxicillin clavulanate.
There is no real benefit to using IV aminophylline. However, if the patient is using theophylline on a chronic basis (in outpatient setting), it should be continued during the exacerbation because abrupt discontinuation may worsen symptoms.
Always avoid opiates and sedatives because they may suppress the respiratory system.
Teaching the patient optimal use of MDIs has been shown to reduce readmission rates.
Prognosis. FEV1 is the best predictor of survival (the higher the FEV1, the better the survival and the less symptomatic the patients). The rate of FEV1 decline may also predict survival because patients with a faster decline will have increased morbidity. Patients that have a FEV1
≤25% will usually complain of dyspnea at rest.
Tobacco cessation is the only means of slowing progression of COPD and the decrease in FEV1.
It is very important that patients with COPD have vaccinations against Pneumococcus with a booster at 5 years and yearly for influenza. Some experts consider the H. influenzae vaccine mandatory.
Going back to our patient, you would likely find decreased DLCO on her PFTs. Treatment of this patient in the acute exacerbation would be systemic steroids, antibiotics, and bronchodilators, with O2 as needed. Treatment once she goes home would be ipratropium inhaler and home O2.
To assess the severity of this patient’s disease, measure FEV1.
Bronchiectasis
A 17-year-old girl is admitted to the hospital with a right lower lobe pneumonia. She gives you a history of recurrent pneumonias, some of which have kept her in the hospital for weeks, and of chronic productive cough that occurs every day. Her parents inform you that she has had “loose stools” since childhood. On the examination she is thin and in distress. There are diminished breath sounds on the right lower lobe with rhonchi.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
343
USMLE Step 2 l Internal Medicine
Clinical Pearl
5–7% of patients with CF initially present in early adulthood.
Consider CF in adult patients with chronic productive cough (symptoms of bronchiectasis), especially if they have history of recurrent sinusitis, nasal polyps, and weight loss. Most males are infertile.
Bronchiectasis is the permanent dilation of small- and medium-sized bronchi which results from destruction of bronchial elastic and muscular elements. Eventually the bronchi become fibrotic. Bronchiectasis can occur secondary to repeated pneumonic processes such as tuber- culosis, fungal infections, lung abscess, and pneumonia (focal bronchiectasis) or when the defense mechanisms of the lung are compromised as in cystic fibrosis and immotile cilia syndrome (diffuse bronchiectasis).
About 50% of patients with primary ciliary dyskinesia will have situs inversus and sinusitis (Kartagener syndrome).
Bronchiectasis should be suspected in any patient with chronic cough, hemoptysis, foul-smelling sputum production, and recurrent pulmonary infections, sinusitis, and immune deficiencies.
Patients will have persistent cough with purulent copious sputum production, wheezes, or crackles.
There is a significant history of recurrent pneumonias that commonly involve gram- negative bacteria, especially Pseudomonas species.
Hypoxemia may occur causing secondary polycythemia.
Early chest x-ray findings may be normal. In advanced cases chest x-ray may show 1- to 2-cm cysts and crowding of the bronchi (tram-tracking). High-resolution chest CT is the best noninvasive test to detect bronchiectasis.
Treatment. Bronchodilators, chest physical therapy, and postural drainage are used to control and improve drainage of bronchial secretions. Give an antibiotic such as trimethoprim sulfamethoxazole, amoxicillin, or amoxicillin/clavulanic acid when sputum production increases or there are mild symptoms. (“Rotating antibiotics” describes choosing a different antibiotic each time to diminish resistance of microorganisms.) Chronic prophylaxis with antibiotics is not recommended.
If the patient exhibits significant symptoms or pneumonia, treat with IV antibiotics that cover gram-negative bacteria, e.g., quinolones, ceftazidime, or aminoglycosides. Consider surgical therapy for patients with localized bronchiectasis who have adequate pulmonary function or in massive hemoptysis.
All patients with bronchiectasis require yearly vaccination for influenza and vaccination for pneumoccocal infection with a single booster at 5 years.
Specific considerations for the treatment of CF include:
Aggressive percussion and lung exercises
Pancreatic enzymes
Supplemental vitamins
Recombinant human DNAse
Inhaled hypertonic saline
Complications include massive hemoptysis, amyloidosis, cor pulmonale, and visceral abscesses.
Going back to our earlier patient, you would treat with antipseudomonal antibiotics (ciprofloxa- cin, ceftazidime). Based on her history, consider a chloride test to diagnose cystic fibrosis.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
344
Chapter 9 ● Pulmonology
Clinical Recall
A 17-year-old boy presents with an acute asthma attack. Which of the following patterns will be seen on an arterial blood gas?
PaCO2 decreased, pH increased, PaO2 normal
PaCO2 decreased, pH decreased, PaO2 increased
PaCO2 increased, pH decreased, PaO2 decreased
PaCO2 increased, pH increased, PaO2 increased
Answer: A
Interstitial lung disease (ILD) is a group of heterogeneous diseases and includes more than 100 disorders. ILD is characterized by chronic inflammation and fibrosis of the interstitium and lung parenchyma. The worst prognosis is with idiopathic pulmonary fibrosis and usual interstitial pneumonitis.
The interstitium of the lung (supporting structure) is the area in and around the small blood vessels and alveoli where the exchange of oxygen and carbon dioxide takes place. Inflamma- tion and scarring of the interstitium (and eventually extension into the alveoli) will disrupt normal gas exchange. Although the progression of ILD may be variable from one disease to another, there are common clinical, radiographic, and spirometric findings.
All patients with ILD develop exertional dyspnea (the most common complaint that brings them to the physician) and nonproductive cough. Examination shows the typical coarse crackles, evidence of pulmonary hypertension (increased pulmonic sound, right heart failure), and clubbing (not always). Chest x-ray is consistent with reticular or reticulonodular pattern (“ground- glass” appearance). PFTs show evidence of intrapulmonary restrictive pattern.
Causes include:
Sarcoidosis
Pneumoconiosis and occupational lung disease
Connective tissue or autoimmune disease–related pulmonary fibrosis
Hypersensitivity pneumonitis
Eosinophilic granuloma (a.k.a. Langerhans cell histiocytosis)
Chronic eosinophilic pneumonia
Wegener granulomatosis
Idiopathic pulmonary hemosiderosis
Bronchiolitis obliterans
Lymphangioleiomyomatosis
Diagnostic evaluation should include high-resolution CT scan and, eventually, biopsy via bronchoscopy or open lung biopsy.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
345
USMLE Step 2 l Internal Medicine
Note
Drugs no longer used in the treatment of IPF include corticosteroids, anticoagulants, interferon, and bosentan.
Idiopathic Pulmonary Fibrosis
A 55-year-old man comes for evaluation of exercise intolerance over the past 6 months. He has no significant past medical history. He informs you that over the past week he cannot walk across the room without getting “short of breath.” He takes no medications and has never smoked. The physical exam is significant for a respiratory rate of 24/min, jugular venous distention ~8 cm, coarse crackles on auscultation, clubbing, and trace pedal edema on both legs. The chest x-ray reveals diffuse reticular disease.
Idiopathic pulmonary fibrosis (IPF) is an inflammatory lung disease of unknown origin that causes lung fibrosis and restrictive lung disease. It characteristically involves only the lung and has no extrapulmonary manifestations except clubbing. Typically seen in decade 5 of life, it affects men and women equally.
Clinical Presentation. Progressive exercise intolerance and dyspnea are seen most commonly. There are coarse dry crackles on auscultation.
Chest x-ray reveals reticular or reticulonodular disease. High-resolution CT may show ground-glass appearance. As IPF progresses, imaging will show extensive fibrosis with honeycomb pattern.
Bronchoalveolar lavage will show nonspecific findings, specifically increased macro- phages.
Lung biopsy will exclude other causes with similar findings, e.g., vasculitis, infections, cancer.
Treatment. Pharmacologic treatment includes pirfenidone, a new small-molecule compound that has antifibrotic effects (shown to significantly reduce a decline in lung function and IPF disease progression). Non-pharmacologic treatment for eligible patients includes lung trans- plantation (shown to reduce the risk of death by 75% as compared with those who remain on the waiting list).
Sarcoidosis
A 27-year-old woman comes to your office with painful erythematous papules that occurred yesterday. She has no other complaints except joint swelling and pain that occurred 3 days ago. Physical examination discloses low-grade fever, symmetric swellingoftheknees, PIP(proximalinterphalangeal) and MCP(metacarpophalangeal) joints, and well demarcated, 3- to 4-cm papules over the anterior aspect of her legs. What is the next step in confirming the likely diagnosis?
Sarcoidosis is a systemic disease of unknown cause, characterized histologically by the presence of nonspecific noncaseating granulomas in the lung and other organs. There is an increased incidence among blacks and patients age 20–40.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
346
Chapter 9 ● Pulmonology
Sarcoidosis can involve almost any organ system, but pulmonary involvement is most com- mon. Ocular, cutaneous, myocardial, rheumatologic, GI, and neurologic manifestations can also occur. Dermatologic manifestations occur in 25% of patients with sarcoidosis; they include lupus pernio, erythema nodosum, non-scarring alopecia, and papules.
Commonly, sarcoidosis is discovered in a completely asymptomatic patient, usually in the form of hilar adenopathy on chest x-ray.
There are 2 distinct sarcoid syndromes with acute presentation:
Löfgren syndrome includes erythema nodosum, arthritis, and hilar adenopathy.
Heerfordt-Waldenstrom syndrome describes fever, parotid enlargement, uveitis, and facial palsy.
Lung involvement in sarcoidosis occurs in 90% of patients at some time in their course. Hilar and left paratracheal adenopathy is the most common presentation. Interstitial lung disease with or without hilar adenopathy can also be a presentation of sarcoidosis.
Figure 9-10. Lupus Pernio Sometimes Seen with Sarcoidosis
Chest x-ray findings can show 4 stages of disease (the stages are not progressive):
Bilateral hilar adenopathy
Hilar adenopathy with reticulonodular parenchyma
Reticulonodular parenchyma alone
Honeycombing of bilateral lung fields with fibrosis
Clinical presentation includes:
Hypercalcemia or hypercalciuria due to increased circulation of vitamin D produced by macrophages
Elevated angiotensin-converting enzyme (ACE) (60% of patients); ACE levels are
nonspecific but can be used to follow the course of the disease
Abnormalities in LFTs (30% of patients with liver involvement, with 90% of patients being symptomatic)
Clinical Pearl
Do not use serum ACE levels to diagnose sarcoidosis.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
347
USMLE Step 2 l Internal Medicine
Clinical Pearl
If a patient is asymptomatic and has bilateral hilar adenopathy on routine chest x-ray, assume it is sarcoidosis and follow with imaging.
Skin anergy
PFTs normal or showing a restrictive pattern
Uveitis and conjunctivitis (>25% of patients) (give all patients with suspected sarcoid- osis an ophthalmologic examination)
The definitive diagnosis of sarcoidosis rests on biopsy of suspected tissues, which show noncaseating granulomas.
Eighty percent of patients with lung involvement from sarcoidosis remain stable, or the sarcoidosis spontaneously resolves. Twenty percent of patients develop progressive disease with evidence of end-organ compromise.
Treatment. There is no evidence that any therapy alters the course of disease. Generally in the setting of organ impairment, a trial of steroids may be used, giving a high dose for 2 months followed by tapering the dose over 3 months. There are certain scenarios in which steroids are mandatory: uveitis, sarcoidosis involving the CNS and heart, and patients who develop hypercalcemia.
The pneumoconioses are occupational lung diseases in which inhalation of certain fibers initiates an inflammatory process and eventually leads to fibrosis of the lung. Usually, pneumo- coniosis appears 20–30 years after constant exposure to offending agents (metal mining of gold, silver, lead, copper), but it can develop in <10 years when dust exposure is extremely high.
History is of primary importance in assessing possible occupational lung diseases.
Pathology. Alveolar macrophages engulf offending agents, causing inflammation and fibrosis of the lung parenchyma in pneumoconiosis. Respiratory insufficiency is the ultimate conse- quence of the pneumoconioses.
Signs and symptoms include dyspnea, shortness of breath, cough, sputum production, cor pulmonale, and clubbing. PFTs show a restrictive pattern with a decreased DLCO. Hypoxemia is evident with an increased PAo2-Pao2 gradient. Chest x-ray findings include small irregular
opacities, interstitial densities, ground glass appearance, and honeycombing.
Asbestosis
Asbestosis is an occupational lung disease caused by prolonged inhalation of asbestos dust. The result is lung parenchymal fibrosis which results in respiratory compromise.
Asbestos fiber exposure may be seen in mining, milling, foundry work, shipyards, or the application of asbestos products to pipes, brake linings, insulation, and boilers.
History of exposure to asbestos is needed to consider the diagnosis.
Signs and symptoms include exertional dyspnea and reduced exercise tolerance, cough and wheezing (especially among smokers), chest wall pain, and ultimately respiratory failure.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
348
Chapter 9 ● Pulmonology
On chest x-ray, diffuse or local pleural thickening, pleural plaques, and calcifications at the level of the diaphragm are seen. Pleural effusions are commonly seen, and the interstitial lung process associated with asbestosis usually involves the lower lung fields.
The most common cancer associated with asbestosis is bronchogenic carcinoma (adenocarci- noma or squamous cell carcinoma).
Pleural or peritoneal mesotheliomas are also associated with asbestos exposure but are not as common as bronchogenic cancer.
For diagnosis, a lung biopsy is usually needed; the classic barbell-shaped asbestos fiber is found.
No specific treatment is offered. Patients with asbestos exposure should strongly be advised to stop smoking since their risk of lung cancer is 75 times higher than that of the normal population.
Silicosis
Silicosis is an occupational lung disease caused by inhalation of silica dust. It is seen in individuals who work in mining, quarrying, tunneling, glass and pottery making, and sandblasting.
Silicosis causes similar symptoms to asbestosis (or any other pneumoconiosis) except the acute form of silicosis, which is caused by massive exposure that causes lung failure in months.
Pathology. Silica causes inflammatory reactions with pathologic lesions being the hyaline nodule.
Chest X-Ray. In silicosis there are nodules (1–10 mm) seen throughout the lungs that are most prominent in the upper lobes. A characteristic finding is eggshell calcifications (rare). In progressive massive fibrosis, densities are 10 mm or more and coalesce in large masses.
Diagnosis is made with lung biopsy. There is no effective therapy for silicosis. Death occurs usually because of progressive respiratory insufficiency.
Coal miner’s lung/coal worker’s pneumoconiosis
The risk of development and progression of coal miner’s lung (CWP) is related to the amount of coal dust exposure, higher rank (hardness) of coals, and increased silica content of inhaled dust. Simple CWP is seen in 12% of all miners.
Patients clinically present as they would with any other occupational lung disease. On chest
x-ray, small round densities are seen in the parenchyma, usually involving the upper half of the lungs. Complicated or progressive massive fibrosis is diagnosed by the presence of larger densities from 1 cm in diameter to the entire lobe. Increased levels of IgA, IgG, C3, antinuclear antibodies (ANA), and rheumatoid factor are also seen.
In Caplan syndrome there are rheumatoid nodules in the periphery of the lung in a patient with rheumatoid arthritis and coexisting pneumoconiosis (usually CWP).
Clinical Correlate Silicosis has an association with pulmonary TB. Patients
with silicosis should have
yearly PPD tuberculin testing; if positive reactive (>10 mm), give isoniazid (INH) prophylaxis for 9 months.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
349
USMLE Step 2 l Internal Medicine
Clinical Recall
A 65-year-old man complains of progressive difficulty breathing for the past 6 months. He has a 30-pack-year smoking history and is suspected of having COPD. Which of the following is the best initial management of this patient?
Antibiotics
Chest CT
Pulse oximetry
Pulmonary function testing
Answer: C
Thromboembolic disease is a common cause of morbidity and mortality in the hospital and outpatient setting and poses a diagnostic challenge even for seasoned clinicians.
Clinically significant pulmonary emboli, for the most part, arise from proximal (above-the- knee) deep vein thrombi (DVT). In turn, most proximal DVT are a consequence of propaga- tion of distal (below-the-knee) DVT. Studies have shown that distal DVT, by themselves, do not pose a risk for the development of a pulmonary embolus. In one-third of the cases, they extend to the proximal veins and thus become a source of pulmonary emboli.
Pulmonary embolism can infrequently occur with upper extremity, subclavian, and internal jugular vein thrombosis. This type of thromboembolic disease occurs in patients when IV catheters are placed in the associated veins. Also, in the pregnant patient, thrombosis may occur initially in the pelvic veins rather than follow the usual course of starting in the distal and then extending to the proximal veins.
Pulmonary embolism and DVT are considered one disease.
Be concerned about (and treat) proximal vein thrombosis because this may result in pulmonary
embolism.
In pregnant patients and those with IV catheters, look for the source of the thromboembolism
in uncommon places (pelvic veins, upper extremity veins, etc.).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
350
Chapter 9 ● Pulmonology
Biomedical Communications 2007—Custom Medical Stock Photo.
Figure 9-11. Unilateral Right Leg Swelling Due to Deep Venous Thrombosis
Natural Course. After a proximal DVT dislodges, it travels through the vena cava and into the right side of the heart. It usually breaks off into multiple thrombi as it goes into the pulmonary circulation, obstructing parts of the pulmonary artery. This results in increased alveolar dead space, vascular constriction, and increased resistance to blood flow. When ~50% of the lung vasculature is involved, significant pulmonary hypertension may occur. This is followed by an increase in right ventricular workload and may lead to right-sided heart failure. A massive pulmonary embolus occurs when >70% of one lung is involved.
About 10% of patients with pulmonary embolus will die within 1 hour of the event, most from a massive pulmonary embolus or significant comorbid conditions (e.g., preexisting CHF or COPD).
When to Consider Pulmonary Embolism and DVTs: High-risk patients
Recent surgery, especially orthopedic surgery (knee replacement surgery carries a 70% risk for DVT)
Cancer history (prostate, pelvic, abdominal, and breast). Note: Studies following patients with unexplained DVT found that 15–20% of these patients developed cancer within the first 2 years after the diagnosis of a DVT.
Immobile patients (especially those hospitalized); patients with significant heart failure; long travel
Clinical Pearl In patients with patent foramen ovale, venous
thromboembolism may result
in embolization involving the systemic circulation. This frequently presents as CVA.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
351
USMLE Step 2 l Internal Medicine
Clinical Pearl
Consider PE in all patients with dyspnea and normal chest radiography.
Acquired thrombophilia, especially lupus anticoagulant, nephrotic syndrome (loss of antithrombin III in the urine), and oral contraceptives (the risk increases further if the patient is a current smoker)
Inherited thrombophilia, of which the most common is factor V Leiden mutation (protein C resistance); others include protein C and S deficiency and antithrombin III deficiency
Pregnancy, for which increased risk for thromboembolism will continue until 2 months after the delivery
Consistent symptoms and signs:
Sudden onset of dyspnea (shortness of breath) and tachypnea
Thigh or calf swelling with or without dyspnea
Pleuritic chest pain
Hemoptysis (occurs only with infarction, which is rare because of the dual circulation [bronchial and pulmonary] that supports lung parenchyma)
On exam, always increased respiratory rate with tachycardia; increased pulmonic sound (P2)
The Wells’ Criteria risk stratifies patients for PE, and has been validated in both inpatient and emergency department settings. While there are other scoring systems for PE and DVT, the Wells criteria are the most widely used in the United States:
Immobilization (≥3 days) or surgery in the previous 4 weeks (1.5 points)
Score <2 = low probability of PE
Tests for the Diagnosis of Thromboembolic Disease
General tests are nonspecific, though they may provide important clues for the diagnosis. They are done routinely in the emergency department in the evaluation of patients with dyspnea.
Arterial blood gas (ABG) tests usually show evidence of hypoxemia with an elevated A-a gradient. In ~10% of patients with documented pulmonary thromboembolism, the A-a gradient may be normal and the hypoxemia mild.
Chest x-ray is very important in finding other causes that may account for the patient’s symp- toms. The most common chest x-ray finding associated with pulmonary thromboembolism is a “normal” chest x-ray. Other nonspecific findings include atelectasis and pleural effusion (transudative and exudative).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
352
Chapter 9 ● Pulmonology
Westermark sign is the lack of vascular markings that occur distal to the pulmonary embolus.
Hampton hump is a wedge-shaped infiltrate (just above the diaphragm) and is due to pulmonary infarction
The ECG may show evidence of right heart strain (due to the development of acute pulmonary hypertension), which manifests as large S waves in lead I and deep Q waves in lead III with
T-wave inversion in the same lead (mnemonic: S1, Q3, T3). The most common finding on the ECG is sinus tachycardia. The ECG is also an important tool in excluding other causes with similar symptoms, specifically acute pericarditis and myocardial ischemia.
Specific tests are more specific for the evaluation of thromboembolic disease (do them when considering the diagnosis).
Figure 9-12. Pulmonary Embolism CT
CT pulmonary angiogram (CT-PA) is the most frequently performed initial test for the diagnosis of pulmonary embolism. It allows direct visualization of the pulmo- nary embolus, and it also allows for the diagnosis of alternative diseases involving the lung parenchyma (pneumonia, pneumothorax, etc.). The older generation of CT-PAs may miss pulmonary emboli that involve the smaller (peripheral) pulmo- nary arteries.
Ventilation-perfusion ( • • ) scan is a pair of nuclear scan tests that use inhaled and
V/Q
injected material to measure breathing (ventilation) and circulation (perfusion) in all areas of the lung. A pulmon•ar•y embolus will typically cause perfusion defects
with normal ventilation. The V/Q scan, depending on the number of defects, is
classified as normal, low probability, intermediate probability, or high probability. Patients that have any preexisting lung disease (COPD)• w•ill have at least intermedi-
ate scans, which make this test less helpful. A normal V/Q scan rules out pulmo-
nary embolus.
Pulmonary angiogram is the gold standard procedure for the diagnosis of pulmo- nary embolus. Its risk of complication (e.g., pulmonary artery rupture) is <1%.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
353
USMLE Step 2 l Internal Medicine
With the new generation of CTs able to visualize the smallest peripheral vessels, the invasive pulmonary angiogram is becoming obsolete.
DVT: compression on duplex U/S (US); venogram (rare); MRI
Both pulmonary embolism and DVT:
D-dimer is the most sensitive test for thromboembolic disease. Elevated D-dimer indicates the presence of an abnormally high level of fibrin degradation products, possibly because of thrombus formation and breakdown. An elevated D-dimer may be due to a thromboembolism, but it may also be due to a recent surgery, infection, trauma, pregnancy, and DIC. Normal D-dimer tests mean that there is no throm- bus formation or breakdown. For the above reasons, a D-dimer can only be used to rule out PE or DVT if the levels are normal. Trials have shown that the D-dimer is most useful when the test is done on patients considered to be low-risk and is recommended as an adjunct test (i.e., a negative D-dimer and a normal CT-PA scan rule out thromboembolism 98% of the time).
There are many types of D-dimer tests with different sensitivities. The ELISA assay is the best test overall, whereas the latex agglutination test is less sensitive.
General diagnostic concepts in patients suspected of pulmonary embolism:
It makes sense to start with a CT-PA after a chest x-ray is completed.
Normal CT scan and normal D-dimer test in low-risk patients excludes pulmonary embolism.
Normal CT scan and normal Doppler U/S in low-risk patients excludes pulmonary embolism.
Even if all tests are negative for pulmonary embolism but the patient is high risk, go for the angiogram.
If a • • scan is completely normal (not near normal or low probability), the chance of
Know how to use Doppler U/S in the evaluation of pulmonary embolism. For exam-
ple, if a • • scan is reported as low probability, still be concerned about pulmonary
embolism. An angiogram is not preferred unless absolutely necessary because it is an invasive procedure. Therefore, do an U/S of both lower extremities to look for a DVT (remember that most pulmonary emboli are complications of DVTs arising in the proximal veins).
All patients (especially high risk) should be on anticoagulation while completing diagnostic evaluations, so start heparin before sending that patient off to the radiology
V/Q
department for the CT or the • • scan.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
354
Anticoagulation
contraindicated
Chapter 9 ● Pulmonology
Diagnosed Pulmonary Embolism
Hemodynamically stable
Hemodynamically unstable
Anticoagulation
contraindicated
Thrombolytic
therapy
Inferior IV or LMW heparin and oral Pulmonary embolectomy vena cava filter anticoagulation (warfarin) 5-7 days and interrupt inferior vena cava
Oral anticoagulation (warfarin)
Figure 9-13. Management of Diagnosed Pulmonary Embolism
Treatment. Give oxygen and start heparin immediately before the diagnosis is confirmed and while the diagnostic workup is being completed. Once the diagnosis is confirmed:
Heparin—LMWH or unfractionated for 5–7 days (or until INR is therapeutic)
In most institutions, LMWH has supplanted the use of unfractionated heparin as the primary heparinoid in the treatment of PE and DVT.
Warfarin (Coumadin®)—should be started with heparin and continued for 6 months for both pulmonary emboli and DVT.
LMWH or fractionated heparin inactivates factor Xa but has no effect on thrombin (no need to follow PTT). Dosing is based on patient’s weight, and the effect is very predictable. The long half-life makes it ideal for a 1× or 2×/day dosing interval. Trials have shown that LMWH is as good as unfractionated heparin in the treatment of DVT and pulmonary emboli; also, LMWH is less likely to cause hemorrhage or heparin-induced thrombocytopenia (HIT).
HIT is a common complication of heparin treatment and occurs 5–7 days after starting treatment in about 5% of patients. Paradoxically, it is associated more with thrombotic events than bleeding diathesis. Always stop heparin when platelets decrease by a significant amount. Also, consider HIT in a patient with recurrent pulmonary embolism or DVT despite heparin treatment. HIT is treated with the new anticoagulants (argatroban, lepirudin).
Warfarin works by inhibiting the vitamin K–dependent factors (II, VII, IX, and X). Because factor VII has the shortest half-life of all the affected factors, prothrombin time (PT) is monitored to assess the warfarin anticoagulant effect. International normalized ratio (INR) is a way to report PT and is used to control for variability in PT between different laboratories. The warfarin dose should be titrated to an INR of 2–3 for effective anticoagulation.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
355
USMLE Step 2 l Internal Medicine
Warfarin skin necrosis is a rare procoagulant effect that occurs in patients who have preexist- ing protein C deficiency and receive warfarin. Protein C is also a vitamin-dependent factor with a shorter half-life than factor VII. A “transient hypercoagulable state” occurs when warfarin is started in patients with subclinical protein C deficiency. This leads to diffuse thrombosis of the skin and other organs. By starting patients on heparin and warfarin at the same time, you minimize the risk for this complication.
Anticoagulation is contraindicated in patients with recent neurosurgery or eye surgery. Consider using an inferior vena cava filter (Greenfield filter) to prevent further embolism in these patients.
Warfarin is contraindicated in pregnant patients. LMWH for 6 months is the best alternative. The patient should have injections once or twice a day.
Thrombolytics (tPA, streptokinase) are not used routinely in pulmonary embolism and should be reserved for patients that become hemodynamically unstable (indicated by hypotension, right heart failure, etc.). In clinical practice, thrombolytics are sometimes also considered in patients with massive DVT to prevent the postphlebitic syndrome.
Although the available vitamin K antagonists are highly effective for the prevention and treatment of most thrombotic disease, significant patient variability in dose response, the narrow therapeutic index, and the numerous drug and dietary interactions associated with these agents have led clinicians to search for alternative agents. These new anti-thrombotic drugs have relatively discrete targets within the coagulation pathway. Two new classes of orally administered anticoagulants, inhibitors of factor X and thrombin inhibitors, have been approved for the management and prevention of venous thromboembolic disease. Rivaroxa- ban is a direct factor Xa inhibitor. Dabigatran is a direct thrombin inhibitor that has been approved for venous thromboembolism prophylaxis.
The postthrombotic syndrome (postphlebitic syndrome) is the most common complication of DVT, occurring in up to two-thirds of patients. It may result from some obstructions that remain in the vein or backflow of blood due to destruction of the valves or both. Signs and symptoms include pain, edema, hyperpigmentation, and skin ulceration. The use of compres- sion stockings has been shown to prevent the postthrombotic syndrome.
Noncomplicated proximal DVTs are usually treated for a total of 6 months.
In patients with thrombophilias (hypercoagulable states), lifelong anticoagulation is considered with warfarin (usually reserved for at least 2 episodes of thrombosis).
Do not check for protein C or protein S deficiency during acute thrombosis. Both warfarin (which the patient should be on) and acute clot formation lower protein C and S.
In patients that develop recurrent thrombosis while on anticoagulants, consider HIT or cancer-related thrombosis (very resistant). Consider placing an inferior vena cava (IVC) filter or using some of the newer anticoagulant classes (e.g., hirudin derivatives). IVC filters are associated with clot formation around the filter site and may cause pulmonary thromboembolism.
Limited distal DVT (below-the-knee DVT) are not themselves a cause of pulmonary embolism, unless they extend to the proximal veins. Management of distal DVT includes 2 options: monitor for possible extension to the proximal veins by using serial U/S or treat with anticoagulation for 3 months.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
356
Chapter 9 ● Pulmonology
Fat embolism is a rare type of embolism that occurs 3 days after long bone fracture (most commonly seen with femur fracture). It may occur, although rarely, after CPR. The clinician should consider this entity with presence of acute dyspnea, petechiae (neck and axilla), and confusion. Treatment is supportive (no anticoagulation).
ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS)
ARDS is defined as an acute lung injury characterized by increased permeability of the alveolar-capillary membrane and pulmonary edema. It eventually leads to severe hypoxemia and decreased pulmonary compliance. Etiology includes sepsis, trauma, disseminated intra- vascular coagulation, drug overdose, inhalation of toxins, Goodpasture syndrome, systemic lupus erythematosus, drowning, and the period after bypass surgery.
ARDS usually occurs within 5 days of the initiating event, and >50% will develop it within the first 24 hours. A major component of ARDS seems to be accumulation of inflammatory cells and their mediators.
Signs and symptoms of ARDS are dyspnea, increased respiratory rate, and diffuse rales and rhonchi on auscultation.
Chest x-ray shows diffuse interstitial or alveolar infiltrates; whiteout of both lung fields may be seen
Swan-Ganz catheter findings reveal normal cardiac output and normal capillary wedge pressure but increased pulmonary artery pressure
Treatment. Treat the underlying disorder. Mechanical support includes increased positive end-expiratory pressure and permissive hypercapnia. Studies have shown that conservative fluid replacement decreased ICU and ventilatory time but mortality remained unchanged. Steroid use is controversial. Mortality rates are approximately 50%.
SLEEP APNEA
Sleep apnea is the cessation of airflow (>10 s) that occurs at least 10−15x per hour during sleep. Oxygen saturation decreases during those apneic episodes, and pulmonary pressures increase.
Daytime somnolence is mandatory for the diagnosis of sleep apnea. Other manifestations include daytime headaches and fatigue. Systemic hypertension also occurs. When severe, sleep apnea will cause pulmonary hypertension and cor pulmonale.
Clinical Pearl Chronic elevation of serum bicarbonate may be seen in
patients with sleep apnea. This
is a response to respiratory acidosis.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
357
USMLE Step 2 l Internal Medicine
There are 2 main classes of sleep apnea:
Obstructive sleep apnea (OSA) occurs because of floppy airways despite adequate ventilatory effort. Patients are usually obese and have abnormal airways. Treatment is weight loss and nasal continuous positive airway pressure (CPAP). When noninvasive measures are not effective, surgical procedures (uvuloplasty) may be considered.
Central sleep apnea (<5%) is caused by inadequate ventilatory drive. Treatment includes conservative measures (weight loss; avoidance of alcohol, sedatives, and sleep deprivation), acetazolamide, progesterone, and supplemental oxygen.
The diagnosis of sleep apnea is based on evaluation of clinical symptoms (daytime sleepiness, fatigue, sleep diary findings, and the results of objective testing with polysomnography.
LUNG CANCER
Bronchogenic carcinoma is the leading cause of death because of malignancy in men and women. The overall 5-year survival rate for small cell cancer is 5% and non-small cell cancer is 8%. The far majority of cases are directly related to cigarette smoking; the occasional non- smoker who has lung cancer develops adenocarcinoma.
Active smokers have 10× greater risk compared with nonsmokers
Risk is directly related to number of pack-years (40-pack-year history increases risk 60–70×)
Those with asbestos exposure have 75x greater risk of bronchogenic carcinoma compared with nonexposed individuals
There is no available screening test for lung cancer at this time.
Pathology. The most common lung cancers are adenocarcinoma (~40% in some studies) and squamous cell carcinoma.
Adenocarcinoma. Adenocarcinoma is a peripherally located lesion. This lesion metastasizes widely to essentially the same sites as small-cell carcinoma. Bronchioalveolar carcinoma is a subtype of adenocarcinoma; it is a low-grade carci- noma that can occur in single or multiple nodules. Asbestos exposure can be an underlying causative agent, usually after a latent period of 30 years. Adenocarcinoma is usually associated with pleural effusions that have high hyaluronidase levels. Diagnosis often requires thoracotomy with pleural biopsy.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
358
Chapter 9 ● Pulmonology
Squamous Cell Carcinoma. Squamous cell carcinoma is a centrally located lesion. It is associated with cavitary lesions. Squamous cell carcinoma usually metastasizes by direct extension into the hilar node and mediastinum. These lesions are associated with hypercalcemia from the secretion of a parathyroid hormone–like substance.
Small-Cell Carcinoma. Small-cell carcinomas are centrally located lesions. These tumors are rapidly growing with early distant metastasis to extrathoracic sites such as liver, adrenal glands, brain, and bone. Prognosis does not improve with early diagno- sis. Small-cell carcinoma is associated with Eaton-Lambert syndrome, syndrome of inappropriate antidiuretic hormone, and other paraneoplastic syndromes. Small-cell carcinoma is also the most common cause of venocaval obstruction syndrome.
Large-Cell Carcinoma. Large-cell carcinoma is a peripherally located lesion. This carcinoma can metastasize to distant locations late in the course of disease. Large-cell carcinoma in early stages is associated with cavitation.
Symptoms. The most common symptom at the time of diagnosis is cough (74%). Weight loss is seen in 68% of patients. Dyspnea is seen in 58% of patients. Other associated symptoms of bronchogenic carcinoma include hemoptysis, chest wall pain, and repeated pneumonic processes (caused by postobstructive pneumonia).
Hoarseness when seen indicates a nonresectable bronchogenic carcinoma.
Diagnosis. The diagnosis of bronchogenic carcinoma can be made by sputum cytology, with the highest yield in patients with squamous cell carcinoma (>80%) because it is intraluminal and centrally located. Bronchoscopy is best for centrally located lesions (yield of 90%) and is helpful in staging. For the 10% of centrally located lesions not detected by bronchoscopy, a needle aspiration biopsy should be performed if carcinoma is highly suspect. In other words, if there is a high degree of suspicion for carcinoma and the bronchoscopy results are nonspe- cific, a biopsy must be requested. Needle aspiration biopsy is also good for peripheral nodules with pleural fluid aspirate (positive in 40–50% of cases). Mediastinoscopy is useful in diagnos- ing and staging mediastinal tumors.
Workup of a chest x-ray with an effusion and a lung mass. 90% of tumors with malignant effusions are unresectable. These tumors are usually adenocarcinomas. Atelectasis on chest x-ray suggests central airway obstruction. Next step in such a patient is to do thoracocentesis and cytologic evaluation of the pleural fluid.
Treatment. Symptoms that suggest an unresectable lesion include weight loss >10%, bone pain or other extrathoracic metastases, CNS symptoms (treated by radiation or chemotherapy), superior vena cava syndrome, hoarseness, mediastinal adenopathy on the contralateral side, split-lung test tidal volume <800 ml, tumor classification of M1 within 3 months, and tumor involving the trachea, esophagus, pericardium, or chest wall.
Resectable lesions of small-cell carcinoma are treated with chemotherapy; VP16 (etoposide and platinum) is the treatment of choice. Surgery is not indicated for these lesions. Non-small- cell lesions that are resectable are treated with chemotherapy and radiation therapy or CAP (cyclo- phosphamide, adriamycin, and platinum). Effusions can be sclerosed with tetracycline. Compli- cations are treated with radiation therapy, which in most cases is palliative.
Prognosis is best after surgical resection of squamous-cell carcinoma (30–35%). Large-cell carcinoma and adenocarcinoma have a prognosis of 25%. Prognosis is poorest for small-cell carcinoma.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
359
USMLE Step 2 l Internal Medicine
Recommendations for lung cancer screening are as follows (see also Preventive Medicine section):
In cases where >30 pack-years of smoking, patients age 55-80 should receive lung cancer screening with low dose CT (non-contrast). The patient has to be a current smoker or has quit >15 years.
In cases where patients age >80, quit >15 years, has other medical problems such as severe COPD which significantly limits life expectancy or ability to undergo surgery, no screening is recommended.
ATELECTASIS
A 62-year-old man is dyspneic 24 h after cholecystectomy. His respiratory rate is 22/min and pulse 112/min. He has a mild fever, and decreased breath sounds are noted in the left lower lobe. Complete blood count shows leukocytosis 27,000/mm3.
Atelectasis is a collapse of part or the entire lung. It is most commonly seen in the immediate postoperative period, often secondary to poor inspiration or lack of coughing. A mucous plug, tumor, or foreign body can also lead to atelectasis.
Acute symptoms include tachycardia, dyspnea, fever, and hypoxemia. In the chronic phase patients may be asymptomatic with only x-ray abnormalities. On x-ray, upper lobe atelectasis can appear as tracheal deviation to the affected side. This phenomenon occurs secondary to volume loss from atelectasis. Lower lobe atelectasis may cause an elevation of the corresponding part of the diaphragm. In massive atelectasis, a mediastinal shift to the involved side can be seen. The atelectatic lobe will appear to be densely consolidated and smaller than the normal lobe on x-ray.
Treatment. In the postoperative phase, it is important to induce deep breathing and stimulate coughing. Incentive spirometry and pulmonary toilet are effective. Bronchoscopy with subsequent removal of mucous plugs is highly effective for spontaneous atelectasis.
A 36-year-old woman presents to the ER complaining of a sudden onset of difficulty breathing. She has a significant smoking history and is suspected of having a pulmonary embolism. Which of the following is the gold standard test for this patient?
ABG
Chest x-ray
D Dimer
Pulmonary angiogram
Pulmonary function testing
Answer: D
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
360
EmergenCchyapMtedr iTciitnle 1#0
Learning Objectives
List the steps to follow in basic life support (cardiopulmonary resuscitation)
Interpret ECG strips to diagnose cardiac dysrhythmias and present the appropriate emergency management
Answer questions about principles of toxicology and initial management with specific management for poisoning or overdose
Describe direct and indirect complications and emergency management of acute/ chronic alcohol use
Describe the emergency management of head trauma, anaphylaxis, subarachnoid hemorrhage, burns, radiation injuries, drowning, and venomous bites/stings
BASIC LIFE SUPPORT (CARDIOPULMONARY RESUSCITATION)
Basic life support is the initial management algorithm of any patient who seems to have become unresponsive. Etiology is a cardiac, neurologic, or toxicologic event leading to markedly dimin- ished responsiveness or loss of pulse.
Most causes of cardiac arrest are related to ventricular rhythm disturbance. The most common etiology of serious cardiac dysrhythmia is ischemia-related, particularly with coronary artery disease or another cardiac anatomic abnormality (especially cardiomyopathy).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
361
USMLE Step 2 l Internal Medicine
Clinical presentation is any patient with diminished responsiveness that is usually sudden in onset.
At first this is a clinically determined diagnosis. The initial step is to assess the patient’s responsiveness, to make sure he is truly unresponsive and not just asleep. Call to or gently shake the patient (but be careful about shaking a patient who might have serious traumatic injury, particularly of the cervical spine).
After determining that the patient is truly unresponsive, call for help (dial 911). Although it is natural to reach down to check a pulse, this is not the action that the USMLE or the American Heart Association wants you to build as a reflex. Without the EKG, defibrillator, and cardiac medications, there is very little a rescuer can do for a patient with a serious dysrhythmia beyond chest compressions and opening the airway.
If a patient has a serious dysrhythmia such as asystole or ventricular fibrillation, there is virtually no survival if the heart has not been restarted within 10 minutes. Chest compressions just perfuse vital organs; they will not convert the arrhythmia back to normal sinus. AHA guidelines emphasize high-quality CPR with uninterrupted chest compressions of adequate depth (5 cm, 2 in.) at 100/min and decreased intervals between stopping the chest compression and shock delivery.
Avoid excessive ventilation as it can be detrimental. ABC, according to new guide- lines, is now CAB (excluding newborns). Removing the 2 rescue breaths allows chest compressions to be delivered sooner. Earlier chest compressions and defibrillation are critical elements of CPR.
After calling for help, position the patient on a firm, flat surface, and roll to be face up. Check for a pulse by feeling for at least 5–10 seconds at the carotid artery. If there is no pulse, perform chest compressions at 100/min, “push hard and push fast.”
Depth of chest compression is 2 in. or 5 cm.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
362
Chapter 10 ● Emergency Medicine
Advanced Cardiac Life Support Algorithms
1
Pulseless Arrest
BLS Algorithm: call for help, give CPR
Give oxygen when available
Attach monitor/defibrillator when available
Check rhythm
Shockable rhythm?
3 2
VF/VT
Give 1 shock Resume CPR | |
Manual biphasic: device specific (typically 120–200 J)
AED: device specific
Monophasic: 360 J
Manual biphasic: immediately
4 
5 
9
Asystole/PEA
Resume CPR immediately for 5 cycles
When IV/IO available, give vasopressor
Repeat every 3 to 5 min
May give 1 dose of vasopressin 40 U IV/IO to replace first or second dose of epinephrine
10 
Give 5 c of CPR*
Continue CPR while defibrillator is charging Give 1 shock Resume CPR immediately after the shock When IV/IO available, give vasopressor during CPR (before or after the shock) Repeat every 3 to 5 min or | |
Manual biphasic: device specific (same as first shock or higher dose; if unknown, use 200 J)
AED: device specific
Monophase: 360 J
Epinephrine 1 mg IV/IO
May give 1 dose of vasopressin 40 U to replace first or second dose of epinephrine
ycles
Shocka
Check rhythm
Shockable rhythm?
Shockable rhythm?
13
ble
Shockable
8
Push hard and fast (100/min)
Ensure full chest recoil
Continue CPR while defibrillator is charging
Give 1 shock
Manual biphasic: device specific (same as first shock or higher dose; if unknown, use 200 J)
AED: device specific
Monophase: 360 J
Resume CPR immediately after the shock, consider antiarrhythmics; give during CPR
(before or after the shock)
amiodarone or lidocaine
Consider magnesium for torsades de pointes
After 5 cycles of CPR,* go to Box 5 above
Minimize interruptions in chest compressions
One cycle of CPR: 30 compressions then 2 breaths; 5 cycles = 2 min
Avoid hyperventilation
Secure airway and confirm placement
After an advanced airway is placed, rescuers no longer deliver “cycles” of CPR. Give continuous chest compressions without pauses for breaths. Give 8–10 breaths/minute. Check rhythm every 2 minutes.
Rotate compressors every
Go to Box 4
2 minutes with rhythm checks
Search for and treat possible contributing factors:
–Hypovolemia
–Hypoxia
–Hydrogen ion (acidosis)
–Hypo-/hyperkalemia
–Hypoglycemia
–Hypothermia
–Toxins
–Tamponade, cardiac
–Thrombosis (coronary or pulmonary
–Trauma
Figure 10-1. ACLS Pulseless Arrest Algorithm
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
363
USMLE Step 2 l Internal Medicine
Note
For asystole and other arrhythmias in this chapter, remember the “Hs and Ts”:
Hypoxia Hyper/Hypokalemia Hypothermia Hypoglycemia Hypovolemia Trauma
Toxins (including overdose)
Tamponade
Tension pneumothorax
Thrombosis (coronary and
pulmonary)
Note
Atropine is no longer indicated in asystole.
Note
Transcutaneous pacemaker is not useful for asystole.
CARDIAC DYSRHYTHMIAS
Asystole
A 54-year-old man is at the opera when he suddenly jumps up and clutches his chest. He falls to his side into the lap of the woman sitting next to him. After confirming that he is unresponsive, a nearby physician performs chest compressions and ventilations. An EKG is done and reveals no evidence of electrical activity.
Asystole is the complete absence of electrical activity in the heart. This does not necessarily mean a completely flat line on an EKG because there may be slight variability on the rhythm strip.
The most common causes of asystole are ischemia and severe underlying cardiac disease; less common causes include metabolic derangements, drug overdose, and trauma.
Clinical presentation includes an unresponsive person with asystole on EKG; there is no pulse. Always confirm asystole by observing the rhythm in more than one lead on EKG.
Treatment. As you continue cardiopulmonary resuscitation (CPR), obtain IV access and prepare the patient for intubation.
Next, administer 1 mg epinephrine via IV push every 3–5 minutes. (Atropine is no longer recommended for asystole.)
If asystole persists, withhold resuscitative efforts in order to evaluate the presence of atypical clinical features or cease-effort protocol.
When you see asystole on the monitor, make sure of the following:
There are no loose or disconnected leads
The power to ECG machine and monitor is on
There is not a low signal gain on the monitor
Note: Bicarbonate is useful if the cause of asystole is attributed to a preexisting acidosis (except hypercarbic acidosis), tricyclic antidepressant overdose, aspirin overdose, hyperkalemia, or diabetic ketoacidosis.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
364
Chapter 10 ● Emergency Medicine
Ventricular Fibrillation
A 54-year-old man is at the opera when he suddenly jumps up and clutches his chest. He falls to his side into the lap of the woman sitting next to him. He is not breathing. After confirming that he is unresponsive, a nearby physician performs chest compressions and ventilations. An EKG is done and reveals ventricular fibrillation. He has no spontaneous respirations.
Ventricular fibrillation is significant electrical activity on EKG with no signs of an organized pattern. The most common causes are ischemia, myocardial infarction, cardiomyopathy, and severe underlying cardiac disease. Remember the “Hs and Ts.”
Presentation is a dead person with ventricular fibrillation on EKG. Diagnosis is entirely based on the EKG.
Treatment. The differences between defibrillation and cardioversion are very important.
Defibrillation is a nonsynchronized delivery of shock at any phase of cardiac cycle. It is used in VF and pulseless VT. During defibrillation you depolarize all of the myocytes simultaneously, hoping that the SA node will start up normal sinus rhythm.
Cardioversion is a synchronized shock with the QRS complex. When performing cardioversion, the defibrillator will not shock until the QRS complex appears. You will be able to see spikes over the QRS complexes on the monitor. If you shock on the T wave, when ventricular repolarization is taking place, you may induce VF.
Make sure that the SYN button is pushed when performing cardioversion. Use UNsynchro- nized shock (defibrillation) for VF or pulseless VT only.
Figure 10-3. Ventricular Fibrillation
Post-Resuscitation Care. Most patients who survive resuscitation have anoxic brain injury. Therapeutic hypothermia reduces the risk of this type of severe neurologic injury. Initiate it if a patient is not following commands or showing purposeful movements. The goal of the protocol is to reach core temperature 32–34° C (90–93° F) within 6 hours and maintain for 12–24 hours. This can be done with ice packs, cooling blankets, or cold IV fluids.
Absolute contraindications for induced hypothermia are active bleeding and do-not-resuscitate order.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
365
USMLE Step 2 l Internal Medicine
1
TACHYCARDIA
with Pulses
2
5
Establish IV access
Obtain 12-lead ECG (when available) or rhythm strip
Is QRS narrow (<0.12 sec)?
4
Perform immediate synchronized cardioversion
Establish IV access and give sedation if patient is conscious; do not delay cardioversion
Consider expert consultation
If pulseless arrest develops, see Pulseless Arrest Algorithm
Symptoms Persist | |
Access and support ABCs as needed
Give oxygen
Monitor ECG (identify rhythm) blood pressure, oximetry
Identify and treat reversible causes
3
Is patient stable?
U
Stable Unstable signs include altered Unstable mental status, ongoing chest pain,
hypotension, or other signs of shock Note: rate-related symptoms uncommon if heart rate <150/min
6 Narrow
NARROW QRS*:
Is rhythm regular?
Regular
WIDE QRS*:
Is rhythm regular? Expert consultation advised
Irregular narrow-complex tachycardia
Probable atrial fibrillation or pos- sible atrial flutter or MAT (multifocal atrial tachycardia)
-blockers; use -blockers with caution in pulmonary disease or CHF)
Attempt vagal maneuvers
Give adenosine
Irregular
If atrial fibrillation with aberrancy, see irregular narrow-complex tachy- cardia (Box 11)
If pre-excited atrial fibrillation (AF + WPW), seek expert consultation
Avoid AV nodal blocking agents (e.g., adenosine, digoxin, diltiazem, vera- pamil)
Consider antiarrhythmics
If recurrent polymorphic VT, seek expert consulta- tion
If Torsades des pointes, give magnesium
If ventricular tachycardia or uncertain rhythm
8
Does rhythm convert?
Note: Consider expert consultation
If rhythm converts, probable reentry SVT (reentry supraventricular tachycardia):
Observe for recurrence
Treat recurrence with adenosine or longer- acting AV nodal blocking agents (e.g., diltiazem,
-blockers)
If rhythm does NOT convert, probable atrial flutter, ectopic atrial tachycardia, or junctional tachycardia:
Control rate (e.g., diltiazem,
-blockers; use -blockers with caution in pulmonary disease or CHF)
Treat underlying cause
During evaluation:
*Note: If patient becomes unstable, go to Box 4.
Secure, verify airway and vascular access when possible
Consider expert consultation
Prepare for cardioversion
Treat contributing factors:
Hypovolemia
Hypoxia
Hydrogen ion (acidosis)
Hypo-/hyperkalemia
Hypoglycemia
Hypothermia
Toxins
Tamponade, cardiac
Tension pneumothorax
Thrombosis (coronary or pulmonary)
Trauma (hypovolemia)
366
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc.
Figure 10-4. Algorithm for Tachycardia with Pulses
and the National Board of Medical Examiners.
Chapter 10 ● Emergency Medicine
Ventricular Tachycardia
A 54-year-old man is at the opera when he suddenly jumps up and clutches his chest. He falls to his side into the lap of the woman sitting next to him. He is awake but disoriented and confused. He is complaining of dyspnea and lightheadedness. His exam reveals jugulovenous distention and blood pressure 114/80 mm Hg. EKG shows ventricular tachycardia at rate 180.
Ventricular tachycardia (VT) is a wide complex tachycardia with an organized, uniform pattern on the EKG. No P-waves are visible. It is most commonly caused by ischemia, myocar- dial infarction, and anatomic cardiac disease. Other possible etiologies include quinidine, tricyclics, phenothiazines, and long QT syndromes.
The dysrhythmia originates from an ectopic focus in the myocardium or from the AV node. When the impulse originates from around the AV node, this is from reentry. The electrical impulses must travel throughout the myocardium, from myocyte to myocyte, without the benefit of the more rapidly conducting normal pathways such as the bundle branches or His-Purkinje fibers.
The slowness of the conduction produces the slower and therefore wider complexes on EKG. The rate most often varies 160–240/min. Torsade de pointes is a form of VT in which the morphology varies with an undulating amplitude, making it seem that it “twists around a point.” Torsade may be associated with hypomagnesemia and preceded by long QT interval.
Symptoms are often related to duration of the dysrhythmia. Short bursts of a few seconds may produce no symptoms at all. VT lasting >30 seconds is referred to as sustained VT. Symptoms include lightheadedness, hypotension, CHF, syncope, and death.
Diagnosis. The EKG shows the VT. For those patients presenting with syncope suspected to be of cardiac origin and in whom an arrhythmia is not visible on the initial EKG, an electrophysi- ologic study can be done to try to elicit the VT.
Note
Medications that prolong QT interval
TCAs
Antipsychotics Macrolides Methadone Fluoroquinolones Amiodarone Quinidine
Class III: sotalol, ibutilide, dofetilide
Procainamide
Causes of prolonged QT and Torsade
Hypothyroidism Hypokalemia Hypocalcemia
Congenital or prolonged QT
syndrome
Note
Amiodarone is superior to lidocaine for VF/VT.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
367
USMLE Step 2 l Internal Medicine
Note
For VT without hemodynamic instability, try procainamide first, amiodarone second, and cardioversion last.
Note
For systolic dysfunction, the only antiarrhythmics that are safe are amiodarone, lidocaine, and dofetilide.
Figure 10-6. Ventricular Tachycardia
Treatment. For those with sustained VT and a pulse who are hemodynamically unstable, immediate synchronized cardioversion is required. Signs of hemodynamic instability requiring cardioversion include hypotension, chest pain, altered mental status, and CHF. A lower dose of electricity, starting at 100 J, can be used at first for monomorphic VT. The cardioversion should be synchronized. Conscious patients should be sedated with midazolam, fentanyl, or morphine before cardioversion.
VT in those patients without a pulse should be managed in the same way as ventricular fibrillation (unsynchronized shock). Stable VT (wide, monomorphic, regular) without serious hemodynamic compromise can be treated medically with antiarrhythmics if no response. In stable patients with pulse, procainamide is the preferred drug, If there is no response, try amiodarone or sotalol, followed by electrical cardioversion.
Magnesium may be useful in general but it is most useful for Torsade de pointes. If magnesium fails to treat Torsade, then try isoproterenol or lidocaine. Overdrive pacing can be used if pharmacologic treatment fails. Patients undergoing cardioversion should be sedated first with midazolam, fentanyl, or morphine. Long-term therapy is most effective with beta-blockers. VT which produces sudden death or VT that is sustained through initial drug therapy may require the placement of an implantable cardiac defibrillator (ICD). All patients with ejection fraction
<35% should have ICD due to increased risk of VT and VF.
Pulseless electrical activity (PEA) is hypotension to the point of losing one’s pulse; there is still some type of electrical activity on the EKG that may even be normal or a simple tachycardia. More than the other dysrhythmias, knowing the etiology PEA is the key to the therapy because the specific therapies are so divergent.
Essentially, the heart may still be beating, but there is no blood in the heart, and therefore there is no cardiac output. Causes of PEA are severe hypovolemia, cardiac tamponade, tension pneumo- thorax, massive pulmonary embolism, and a massive myocardial infarction. Other causes in which there may not be actual muscular contraction are hypoxia, hypothermia, potassium disorders, acidosis, and drug overdoses with tricyclics, digoxin, beta-blockers, or calcium-chan- nel blockers.
The patient appears to be dead with no pulse. Other symptoms are based on the specific nature of what led to the PEA, such as those described. Diagnosis is made with a pulseless patient who has significantly organized, and occasionally normal, activity on EKG.
Treatment. The most important action is to maintain CPR while determining the specific origin of the PEA. General therapy includes CPR, IV access, intubation, and epinephrine. Do not shock PEA arrest. The most important therapy is repair of the cause. Bicarbonate is useful
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
368
Chapter 10 ● Emergency Medicine
if a known acidosis has caused the arrest; it can also be used in a prolonged resuscitation if severe lactic acidosis develops and causes the refractory state of arrest. Pericardiocentesis may be attempted if all else fails.
Clinical Recall
Which of the following disorders is not an indication for cardioversion?
Atrial fibrillation
Atrial flutter
Electromechanical dissociation
Ventricular tachycardia
Atrial Dysrhythmias
A 24-year-old medical student is brought to the emergency department because of palpitations. He has been studying vigorously for the USMLE Step 2 exam and has been up for the last 24 hours. He has had 5 cups of coffee, 4 beers, 3 stimulant tablets, 2 cheeseburgers, and 1 Viagra. Electrocardiogram reveals an atrial dysrhythmia.
Atrial fibrillation (A-fib), atrial flutter, and supraventricular tachycardia (SVT) are all characterized by an ectopic focus in the atrium or re-entry at the AV node.
All have normal conduction in the ventricular myocardium once the impulse successfully passes the AV node and travels down the normal ventricular conduction system.
All have a normal or narrow QRS complex and the absence of a normal P-wave.
A-fib is caused by chronic hypertension (most common), but valvular heart disease (most often mitral valve pathology), left ventricular hypertrophy, cardiomyopathy, atrial fibrosis, atrial dilation, CAD, and CHF are other causes. Another cause is toxicity causing overstimulation of the heart, i.e., hyperthyroidism, pheochromocy- toma, caffeine, theophylline, alcohol, and cocaine. Drug toxicity (such as digoxin), pericarditis, pulmonary embolism, surgery, chest wall trauma, or ischemia can also cause atrial dysrhythmias.
SVT is caused by a re-entrant mechanism around or within the AV node.
Clinical Presentation. Symptoms vary on the basis of the duration of the disorder, the ven- tricular rate, and the underlying health of the heart.
With a normal heart, only 10–20% of cardiac output is directly derived from the contribution of atrial systole.
With a dilated or postinfarction heart, or with significant valvular disease, this contribution may rise to 30–40%, in which case more severe symptoms arise: from
Note
A-fib, atrial flutter, and SVT are discussed as a group because their initial management has considerable overlap.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
369
USMLE Step 2 l Internal Medicine
Note
Narrow complex tachycardia is always atrial in origin (QRS <0.12).
Wide complex tachycardia can be atrial or ventricular in origin.
complete absence to palpitations to lightheadedness, hypotension, disorientation, CHF, and syncope.
Rate-related symptoms are unlikely in those with heart rate <150 per minute in atrial dysrhythmia.
Narrow complex tachycardia is always atrial in origin (QRS <0.12). Wide complex tachycardia can be atrial or ventricular. For example, it is very difficult to distinguish A-fib in the presence of LBBB and VT. The key is that in A-fib with LBBB, the rate is irregular on EKG, whereas in VT it is regular. If in doubt, treat as VT.
Diagnosis. Initially, the diagnosis is based entirely on the EKG. Other patients may need a 24–72 hour Holter monitor to detect brief paroxysms of the dysrhythmia not seen on the initial brief EKG.
Figure 10-7. Normal Sinus Rhythm
Figure 10-8. Atrial Tachycardia
Figure 10-9. Atrial Flutter
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
370
Chapter 10 ● Emergency Medicine
Figure 10-10. Atrial Fibrillation
Treatment. Initial therapy is based on whether there are signs/symptoms of severe hemody- namic compromise, such as hypotension, confusion, CHF, or chest pain. If there are signs, perform immediate synchronized cardioversion.
If the patient is hemodynamically stable, then the first step is to control the ventricular rate. For SVT, a vagal maneuver such as carotid sinus massage, Valsalva, or ice water immersion is most effective.
The modified Valsalva maneuver is more effective than the standard technique: do Val- salva followed by supine repositioning and immediate passive leg raise.
Do not do carotid massage on patients with carotid bruits.
If vagal maneuvers do not work, treat SVT with several rapid IV infusions of adenosine. (Do not use adenosine in patients with asthma or COPD, as it can cause bronchospasms.)
If adenosine is not effective, use a calcium-channel blocker (diltiazem or verapamil), beta- blocker, or digoxin to slow the heart rate.
Do not use verapamil in patients with severe left ventricular dysfunction and low ejection fraction.
Be cautious using beta-blockers in patients with a history of reactive airway disease.
After the rate has been lowered <110/min, conversion of the rhythm to normal sinus does not need to be routinely done. Chronic rate control with anticoagulation with warfarin to INR 2–3 is superior to converting the patient into sinus rhythm. Returning the patient to a normal sinus rhythm is preferable because chronic A-fib can result in embolic stroke (5–7% of patients per year).
Amiodarone, ibutilide, propafenone, and dofetilide can all convert a minority of patients to sinus rhythm. (At the level of the Step 2 exam, you will not need to know much about the specific indications for each, though you will need to know that elective cardioversions should be preceded and followed by several weeks of anticoagulation with coumadin.)
Avoid adenosine in asthma and COPD, as it can cause bronchospasms.
Rate Control vs. Rhythm Control. When patients present in A-fib with rapid ventricular response, hemodynamic stability must first be determined.
If hemodynamically stable: rate-control with AV nodal blocking agents
If unstable, do immediate synchronized cardioversion
Note
Palpitations and lightheadedness are not signs of hemodynamic compromise.
Note
For patients with A-fib and flutter, give rate control treatment plus anticoagulation (aspirin, warfarin, etc). When warfarin is used, optimal INR therapeutic range is 2.0−3.0.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
371
USMLE Step 2 l Internal Medicine
Note
CHADS2−VASc score
CHF: 1 point
HTN: 1 point
Age ≥75: 1 point (age 65−74:
1 point)
DM: 1 point
Prior stroke/TIA: 2 points Female sex: 1 point
Vascular disease (CAD, PAD):
1 point
Note
If a patient doesn’t want to check INR or has difficulty staying in therapeutic range, give a newer agent.
With long-term management, rate control and anticoagulation are preferred over rhythm con- trol. Consider rhythm control for the following:
Symptomatic patients on rate control (poor exercise tolerance)
Younger patients with normal heart structure and function
Patients unable to be rate controlled with AV nodal blocking agents
It is very difficult to keep patients with structural heart disease in normal sinus rhythm. Several studies have shown an increase in overall mortality with rhythm control. Catheter- directed ablation of the AV node or accessory pathway may be used when pharmacological treatment fails to control rate.
The rate control goal is HR <110/min. Diltiazem, beta blockers, verapamil, and digoxin may help.
Most patients require combined therapy: beta blockers with digoxin have been shown to be best combination
In patients with decompensated CHF: use digoxin first and amiodarone as second-line therapy; start beta blockers once patient is euvolemic on exam but use caution
Agents for chemical cardioversion in A-fib include amiodarone, dofetilide, flecainide, ibutilide, propafenone. In CHF patients, use amiodarone and dofitelide only.
Agents for maintaining sinus rhythm include flecainide, propafenone, sotalol, dronedarone, dofetilide, and amiodarone. To maintain normal sinus rhythm in CHF patients, use only amiodarone or dofetilide. In patients with coronary artery disease and normal EF, dofetilide, dronedarone, and sotalol are first line over amiodarone.
The CHADS2−VASc score is used to determine if a patient with non-valvular A-fib needs anticoagulation.
Give aspirin or anticoagulation | |
Dabigatran is an oral direct thrombin inhibitor shown to reduce the incidence of ischemic stroke compared with warfarin, with similar rates of bleeding. Rivaroxaban is an oral factor Xa inhibitor. For anticoagulation, use coumadin, dabigatran, or rivaroxaban. Apixaban, another oral factor Xa inhibitor, may be used instead of coumadin for stroke prophylaxis in patients with a-fib and high risk of stroke (CHADS2 score ≥2).
All 3 drugs—dabigatran, rivaroxaban, and apixaban—lead to similar or lower rates both of ischemic stroke and major bleeding compared to coumadin; there is no need for monitoring INR.
Other advantages of these newer agents include convenience (no requirement for routine testing of the international normalized ratio), 50% less intracranial bleed than warfarin, and less susceptibility to dietary and drug interactions. Disadvantages include lack of an antidote and the potential that new side effects may be seen over time.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc.
and the National Board of Medical Examiners.
372
Chapter 10 ● Emergency Medicine
For patients undergoing elective cardioversion, first determine if they have been in A-fib for
>48 hours. If they have, there are 2 options:
Transesophageal echo can be done to exclude a clot; then, cardioversion (electrical or chemical). Cardioversion should be followed by 6 weeks of coumadin.
Coumadin can be administered for 3 weeks before electrical or chemical cardiover- sion. Cardioversion should be followed by another 6 weeks of coumadin.
It is very difficult to maintain patients with structural heart disease in NSR, and most convert back into atrial fibrillation. Atrial flutter is managed the same way as atrial fibrillation.
For patients in A-fib with Wolff-Parkinson-White syndrome, administration of drugs which slow AV node conduction (Ca-channel blockers, digoxin) is strongly contraindicated as they can induce VT. Procainamide, ibutilide, flecainide, or amiodarone can be used in such cases.
If none of the medications described can successfully convert the patient to a normal sinus rhythm, then elective electrical cardioversion can be attempted. This too must be preceded and followed by several weeks of anticoagulation if the A-fib has been present for >48 hours.
Transesophageal echo can be done to exclude a clot and allow the cardioversion without preconversion anticoagulation. Neither medical nor electrical cardioversion can permanently maintain the majority of patients on sinus rhythm. Most convert back into atrial fibrillation.
Bradycardia
Sinus bradycardia can be a normal phenomenon, particularly in trained athletes. Medications such as beta-blockers can cause it without serious sequelae. Symptomatic sinus bradycardia from sinus node disease can be from degeneration of the node or from ischemia.
More serious types of bradycardia can be from Mobitz type II second-degree heart block and third-degree (complete) heart block. These can occur secondary to ischemic damage of the AV node. Other causes are myocarditis, infiltrative disease, such as amyloidosis or sarcoidosis, or neoplasms.
Clinical presentation can range from the lifelong absence of symptoms to severe symptoms of hypotension and decreased cardiac output. Diagnosis is made with EKG
Note
Patients with A-fib and thyrotoxicosis always get anticoagulation until euthyroid and back in NSR.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
373
USMLE Step 2 l Internal Medicine
Note
Mobitz type I second-degree block is characterized by progressive P-R lengthening, whereas in Mobitz-type II, the P-R interval remains constant.
Note
In the acute setting, transcutaneous pacing is always preferred over transvenous pacing.
Note
If the patient is on a beta blocker, give glucagon. If the patient is on a calcium channel blocker, give calcium.
Figure 10-11. First-Degree Heart Block
Figure 10-12. Second-Degree Heart Block
Figure 10-13. Complete Heart Block
Treatment. Asymptomatic sinus bradycardia, first-degree AV block, and Mobitz type I (Wenckebach) second-degree AV block often need no specific therapy. Any form of severe symptomatic bradycardia is treated initially with atropine and then a pacemaker, if there is no improvement in symptoms.
Mobitz type II second-degree block and third-degree block require the placement of a pace- maker, even in the absence of symptoms. Dopamine or epinephrine is used to improve blood pressure if there is still hypotension after the use of atropine.
For symptomatic sinus bradycardia, treatment is atropine. If atropine fails, then use transcuta- neous pacing.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
374
Chapter 10 ● Emergency Medicine
1
BRADYCARDIA
Heart rate <60 bpm and inadequate for clinical condition
2
Maintain patent airway; assist breathing as needed
Give oxygen
Monitor ECG (identify rhythm), blood pressure, oximetry
Establish IV access
3
Signs or symptoms of poor perfusion caused by the bradycardia?
(e.g., acute altered mental status, ongoing chest pain, hypotension, or other signs of shock)
Observe/Monitor
Perfect for transcutaneous pacing; use without delay for high-degree block (type II second-degree block or
third-degree AV block)
Consider atropine while awaiting pacer; if ineffective, begin pacing
Consider dopamine infusion while awaiting pacer or if pacing ineffective and blood pressure is low
Prepare for transvenous pacing
Treat contributing causes
Consider expert consultation
Figure 10-14. Algorithm for Bradycardia
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
375
USMLE Step 2 l Internal Medicine
Clinical Recall
Which of the following medications causes a prolongation of QT interval?
Amoxicillin
Erythromycin
Isoniazid
Vancomycin
Answer: B
TOXICOLOGY
The initial evaluation of a patient who has been poisoned involves attempting to find out the nature of the toxin ingested. At the same time, history and physical examination can provide clues to the nature of the toxin. In the patient described here, the key issue is the short time between the ingestion and his arrival in the emergency department. He is awake.
Toxidromes are clinical syndromes which suggest a specific class of poisoning, each with asso- ciated physical findings:
Clonidine, barbiturates, opiates, cholinergics, pontine stroke: miosis
Sympathomimetics, anticholinergics: mydriasis
Anticholinergics: dry skin
Cholinergics, sympathomimetics: wet skin
Barbiturates, carbon monoxide poisoning: blisters
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
376
Chapter 10 ● Emergency Medicine
Toxic Ingestion or Overdose
Gastric emptying is rarely, if ever, utilized. In ingestion of an unknown type, perform a urine or blood toxicology screen, but do not delay the administration of antidotes, charcoal, or gas- tric emptying (rarely needed).
Charcoal. The mainstay of therapy is activated charcoal administration. Repeat dose every 2–4 hours to block further absorption of the substance and accelerate the removal of already absorbed toxins from the body. Charcoal is safe for all patients.
Induced vomiting. Ipecac can be used only within 1–2 hours after ingestion, so it has no use in the hospital setting. Very few people arrive within the first hour. Therefore, it is more useful for ingestions in the home, where the time period since ingestion is short and there are no other effective modalities available. Ipecac is never recom- mended for use in children.
Lavage. Gastric emptying with a large-bore (37-42 French) oropharyngeal hose (e.g., Ewald tube) should be used only in those with an altered mental status and in whom ipecac is dangerous because of possible aspiration. Lavage should therefore be pre- ceded by endotracheal intubation.
Whole bowel irrigation. For large-volume pill ingestions in which the pills can be seen on an x-ray, whole bowel irrigation can be effective. A gastric tube is placed and high-volume (1–2 liters per hour) GoLYTELY (polyethylene glycol) is administered until the bowel movements run clear.
Dialysis. Dialysis is rarely necessary because the time delay to its initiation limits its efficacy. If it is necessary, hemodialysis is 20x more efficacious at removing drugs from the body than peritoneal dialysis. Dialysis is your answer when there are profoundly serious symptoms such as coma, hypotension, or apnea, especially when renal or hepatic failure limits the usual means of excreting substances from the body.
Cathartics. Cathartics are useful when used with charcoal administration. Otherwise, they are almost never helpful. When you see cathartics in the answer, it is generally the wrong answer.
Forced diuresis. Alkaline diuresis can help eliminate salicylates and phenobarbital. Otherwise, simply making the patient urinate in high volumes is not helpful. Except for salicylates and phenobarbital, forced diuresis is generally the wrong answer.
Naloxone/dextrose/thiamine. These agents should be given first to anyone presenting with altered mental status or coma. They are particularly useful in any toxin ingestion that produces confusion. Naloxone has almost no adverse effects and works instantly. Because of its rapid response, naloxone is both therapeutic and diagnostic. Dextrose is also very effective at preventing permanent brain damage from hypoglycemia. It does not matter whether the dextrose or thiamine is given first.
Note
Ipecac is never used by physicians.
Lavage has almost no utility.
Note
Charcoal does not bind to some substances (PHAILS):
Pesticides Heavy metals
Acid/alkali/alcohol Iron
Lithium Solvents
Note
Substances/drugs that may require hemodialysis for removal include (I STUMBLE):
Isopropanol Salicylates Theophylline Uremia Methanol Barbiturates Lithium Ethylene glycol
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
377
USMLE Step 2 l Internal Medicine
Treat any toxin-related seizure with benzodiazepines as first-line therapy. If not effective, use barbiturates next. Phenytoin and fosphenytoin are not indicated or even effective for this type of seizure.
Toxicology Screen
Toxicology screen is a testing used to determine the approximate amount and type of legal and/or illegal drugs a person has taken. It is used to screen for drug abuse, monitor a sub- stance abuse problem, and evaluate drug intoxication for overdose.
The best initial test in toxicology screen is the urine immunoassay (qualitative test). Typically screened are alcohol, cocaine, PCP, amphetamines, and cannabinoids.
The confirmatory test is gas chromatography/mass spectrometry, which provides qualitative analysis and allows identification of the specific drug or its metabolites.
Toxicology screen must be done within a certain amount of time after the drug is taken, or while metabolites can still be detected in the body. Some examples of clearance time are:
2−4 days; up to 10−22 days with high level use | |
Tetrahydrocannabinol (THC) | 6−11 wks with heavy use |
ACETAMINOPHEN
A 38-year-old man comes to the emergency department 4 days after ingesting a full bottle (60 tablets) of acetaminophen (500 mg each). He complains of vomiting and right upper quadrant pain. Bilirubin, AST, and prothrombin time are all elevated.
378
Acetaminophen is one of the few toxins about which precise toxicity levels are known; the ingestion of ~140 mg per kg is usually sufficient to cause serious toxicity. In other words, in an average-sized, 70-kg (154-lb) person, ~7–10 grams is enough to produce toxicity, and fatalities can occur >12–15 grams. In those with liver disease or concomitant alcohol abuse and thus depleted glutathione stores, the hepatotoxic dose is less (4 grams/day).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
Chapter 10 ● Emergency Medicine
Clinical Presentation.
Stage I (first 12–24 hrs): As with most large-dose pill ingestions, initial symptoms are nausea and vomiting, caused mostly from a gastritis caused by irritation from the pills.
Stage II (24–72 hrs): An asymptomatic period often follows, as the acetaminophen is metabolized and part of the drug is converted to a toxic metabolite.
Starting at 24–48 hrs, subclinical elevation of the transaminases and bilirubin develops.
At 48–72 hrs post-ingestion, clinically symptomatic signs of liver damage begin: more nausea, jaundice, abdominal pain, and signs of hepatic encephalopathy, renal failure, and death.
Diagnosis. A clear history of a large volume of acetaminophen ingestion is initially sufficient to establish a diagnosis that warrants therapy with N-acetyl cysteine (NAC). Starting at 4 hours after ingestion, when most of the drug has been absorbed, drug levels are reliable. A nomo- gram based on relating the drug level to the time of ingestion is necessary to determine who will develop toxicity. In other words, a level by itself is not enough to determine who will develop toxicity. A certain level at 5 or 6 hours may not be toxic; however, the same level at 10–12 hours after ingestion may lead to the development of liver failure.
Elevated AST is more common than elevated ALT. If a patient is known for alcohol abuse and presents with AST and ALT >500 U/L, the diagnosis is more likely to be acetaminophen toxicity than alcoholic hepatitis. Give NAC in such cases.
Elevated bilirubin and prothrombin time indicate severe toxicity and hepatic necrosis. Studies show that NAC administration within the first 8 hours of severe drug poison- ing improves liver microcirculation and prevents the need for liver transplant.
Treatment. NAC is preferably given within 8 hours of ingestion, when it is most effective. If >24 hours has elapsed since ingestion, there is no specific therapy which can prevent or reverse the toxicity, but always still give NAC. Give activated charcoal in repeated doses. Do not use gastric emptying because it will delay the administration of NAC as a specific antidote.
ALCOHOLS
At the opera, you go to see the Three Tenors, who exhibit confusion, ataxia, lethargy, drowsiness, and slurred speech; which is to say, you have really gone to see the Three Drunken Tenors. How would you distinguish between the tenors drunk on methanol or ethylene glycol from those drunk on simple ethanol?
Methanol (wood alcohol) is found in paint thinner, sterno, photocopier fluid, solvents, and windshield washer solution. Ethylene glycol is found in automotive antifreeze. All of the alcohols are metabolized by alcohol dehydrogenase, which then metabolizes methanol to formaldehyde and formic acid. Ethylene glycol is metabolized partially to oxalic acid and oxalate, which leads to kidney damage.
Note
NAC is now used for non- acetaminophen drug-induced liver injury, e.g., amoxicillin/ clavulanate.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
379
USMLE Step 2 l Internal Medicine
Note
Methanol, ethylene glycol, and isopropyl alcohol ingestion will all result in an osmolar gap.
Note
Charcoal will not inhibit the absorption of alcohols. Do not use.
Note
In Northern climates, space heaters during wintertime are a common cause of carbon monoxide poisoning. The most common symptom is headache, along with nausea.
Clinical Presentation. Methanol, ethylene glycol, ethanol, and isopropyl alcohol can all pro- duce intoxication.
Methanol is characteristically associated with visual disturbances up to and including blindness from the production of formic acid.
Ethylene glycol is distinguished by the development of renal failure and oxalate crystals and stones in the urine.
Isopropyl alcohol ingestion is distinguished only once a specific drug level is done by the history or once acidosis has developed in the absence of an elevated anion gap.
Diagnosis. Determining specific levels of each alcohol is the most specific test.
Methanol and ethylene glycol will be characterized by an increased serum osmolar gap and metabolic acidosis with an elevated anion gap.
Ethylene glycol is characterized by oxalate crystals in the urine, increasing BUN/ creatinine, or urine fluorescence (add fluorescein to the urine and observe with ultraviolet Wood’s lamp). Hypocalcemia may also be present.
Isopropyl alcohol will produce an osmolar gap without an increased anion gap.
Treatment. Fomepizole (alcohol dehydrogenase inhibitor) is the drug of choice; it inhibits the production of toxic metabolites without leading to intoxication. Consider dialysis for those with severe anion gap metabolic acidosis or signs of end-organ damage (coma, seizures, renal failure).
In the past, methanol and ethylene glycol intoxication were treated with ethanol infusion (to prevent the production of the toxic metabolites), followed by hemodialysis to remove the substance from the body.
You are the chief resident at a great metropolitan training program at the time of a fire at a large office building. A total of 2,500 people come to your emergency department at the same time to be treated for smoke inhalation. Among them is a 68-year-old man with a history of aortic stenosis who had to walk down 90 flights of stairs. What is the most important initial test for this man?
Poisoning with carbon monoxide (CO) occurs by exposure to burning materials (gasoline, wood, natural gas) and by entrapment in fires and smoke inhalation. Low levels of CO poi- soning are present in most tobacco smokers. CO itself is odorless and tasteless.
CO binds to hemoglobin 200 times more avidly than oxygen.
Carboxyhemoglobin decreases release of oxygen to tissues and inhibits mitochondria, resulting in tissue hypoxia and anaerobic metabolism (similar to what would occur with anemia).
Clinical Presentation.
Pulmonary symptoms include dyspnea, tachypnea, and shortness of breath.
Cardiac symptoms include chest pain, arrhythmia, and hypotension.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
380
Chapter 10 ● Emergency Medicine
Early neurologic symptoms include headache (most common), nausea, blurry vision, and dizziness, while late symptoms include confusion, seizures, impaired judgment, and syncope.
Carboxyhemoglobin (COHb) levels can give an indication of the severity of the exposure.
<10% Levels up to 10% may occur in city dwellers who are smokers
20–30% Mild symptoms
30–50% Moderate to severe symptoms
>50–60% May be fatal
Carbon monoxide pulse oximetry is the initial diagnostic test for suspected CO poisoning, as it provides a way to measure carboxyhemoglobin. Routine pulse oximetry is not helpful.
Influenza is the most common misdiagnosis because most people present during wintertime. When an entire family presents with “flu” symptoms without fever, think CO poisoning.
Arterial or venous blood gases: metabolic acidosis is present from the failure of carboxyhemoglobin to release oxygen to tissues; pO2 will be normal
The first step in treatment is removal from the source of exposure and 100% oxygen adminis- tration. Give hyperbaric oxygen in severe cases: COHb >25% (pregnant women >15%); myocardial ischemia; EKG changes; CNS abnormalities other than headache or chest pain.
In room air, carbon monoxide has a half-life of 4–6 hours, which decreases to 40–80 minutes on 100% oxygen and to 15–30 minutes with hyperbaric oxygen.
Caustics/corrosives are the oral ingestion, inhalation, or cutaneous or ocular contact with various corrosive substances. The most common household acids are various toilet, drain, swimming pool, and metal cleaners. The most common alkali ingestions or exposures are from liquid and crystalline lye, dishwasher detergent, hair relaxer, and oven cleaner. The most common serious injury is from the oral ingestion of liquid drain cleaner.
Symptoms from ingestion injury include the following:
Oral pain
Drooling
Odynophagia
Abdominal pain
Possible esophageal injury with subsequent stricture formation (from either acid or alkali ingestion)
Possible gastric perforation
In most circumstances, alkali exposures are more serious than acid exposures, since alkaline substances are more destructive to tissues.
The history of exposure with subsequent characteristic injury is sufficient to establish the diagnosis. Upper endoscopy is critical for determining the extent of the injury.
Note
CO poisoning initially presents just like hypoglycemia. If fingerstick glucose is normal, that should raise your suspicions.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
381
USMLE Step 2 l Internal Medicine
Treatment. Management of both acid and alkali caustic ingestions is essentially the same.
Wash out the mouth immediately with large volumes of cold water.
Irrigate ocular exposures with large volumes of saline or water, followed by fluores- cein staining to determine if there is significant corneal injury.
Do not induce emesis with acid or alkaline ingestion because it can worsen the injury. Simply give water.
Do not try to neutralize the acid with a base or a base with an acid because a heat- producing reaction can occur, which would destroy more tissue.
Charcoal is not useful, nor are steroids or prophylactic antibiotics.
DRUGS OF ABUSE
Opiate toxicity is predominantly respiratory related, via depressant effects upon the respiratory centers in the brain stem. Death can occur through acute respiratory acidosis. In addition to their analgesic and euphoric effects, opiates also cause pupillary constriction, constipation, bradycardia, hypothermia, and hypotension.
Opiates can be rapidly reversed by naloxone. Since opioids decrease gastric emptying by relaxation of smooth muscle, gastric lavage may be used in cases of overdose with oral agents.
Although withdrawal of opiates is uncomfortable, it is not fatal. It is usually treated with methadone or buprenorphine. Opiate withdrawal symptoms are the following.
8–14 hours: insomnia, yawning, rhinorrhea, diaphoresis, mydriasis, anxiety
1–3 days: tremor, muscle spasms, vomiting, diarrhea, tachycardia, chills, piloerection
Cocaine blocks the reuptake of norepinephrine and other catecholamines at the synapse. This leads to a wide variety of euphoric and toxic effects. Amphetamines work in a similar way but are less likely to produce severe toxicity or death. Severe toxicity from cocaine is far more likely with smoked (“crack”) or injected cocaine rather than snorted (inhaled).
Clinical Presentation. Toxic effects of cocaine are related to a very significant alpha-adrener- gic stimulatory effect, resulting in the following (may lead to death):
Very high BP
Hemorrhagic stroke
Subarachnoid hemorrhage
Myocardial infarction
Arrhythmia
Seizures
Metabolic acidosis, rhabdomyolysis, and hyperthermia in some cases
Pulmonary edema (specific to smoked cocaine)
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
382
Chapter 10 ● Emergency Medicine
Treatment. There is no specific drug to reverse cocaine toxicity. Benzodiazepines such as diazepam are used to control acute agitation. Combined alpha/beta agents such as labetalol or alpha-blockers such as phentolamine are useful to control hypertension. Avoid pure beta- blockers because they lead to unopposed alpha stimulatory effects.
Cocaine withdrawal can cause depression as a result of the norepinephrine depletion. There is limited physiologic withdrawal from cocaine.
Benzodiazepines
Benzodiazepines (BZDs) produce somnolence, dysarthria, ataxia, and stupor. Very infre- quently, they lead to death from respiratory depression; most deaths are associated with ethanol or barbiturate ingestion.
Patients receiving prolonged parenteral administration of BZDs are at risk for propylene glycol poisoning (used in parenteral formulations of diazepam and lorazepam). Rarely, this may cause hypotension, cardiac dysrhythmias, lactic acidosis, seizures, or coma.
Treatment. Good supportive care and monitoring are the foundation of treatment. As with any overdose, the first step is to stabilize the patient’s airway, breathing, and circulation.
Flumazenil is a specific antidote for BZD poisoning, although its use in acute BZD overdose is controversial.
In long-term BZD users, flumazenil may precipitate withdrawal and seizures.
In BZD use for a medical condition, flumazenil may exacerbate the condition.
BZD withdrawal can be similar to the symptoms of alcohol withdrawal. Although rare, deaths have been reported from severe withdrawal. The recommendation for treatment of severe forms of withdrawal is the administrations of BZDs.
Barbiturates
Barbiturates are a class of drugs with various long- and short-acting agents. Massive overdose can result in death from respiratory depression or CNS depression.
Can cause hypothermia, loss of deep tendon reflexes, and loss of corneal reflexes
Could result in a coma simulating brain death
May lead to absent EEG activity
Withdrawal may result in seizures similar to alcohol or benzodiazepine withdrawal
Have no specific antidote, although urinary excretion of phenobarbital can be increased with the use of bicarbonate (similar to treatment for salicylate intoxication)
Hallucinogens
Hallucinogens include a variety of agents such marijuana, LSD, mescaline, peyote, and psilocy- bin. Although they may cause delirium and bizarre behavior, the adverse effects are often limited to their anticholinergic effects: flushed skin, dry mouth, dilated pupils, and urinary retention.
The only hallucinogen associated with a potentially fatal outcome is the artificially created, dissociative, anesthetic phencyclidine (PCP or “angel dust”), which may cause seizures.
Treatment for severe hallucinogen intoxication is with benzodiazepines.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
383
USMLE Step 2 l Internal Medicine
Note
Think lead in patients who have both microcytic anemia and abdominal pain.
Clinical Recall
A 19-year-old man is brought to the emergency room in an unconscious state after consuming an unknown substance at a party. The initial management of this patient should involve which of the following?
CT scan of the brain
Intubation
IV insulin
Naloxone/dextrose/thiamine
Video EEG
Answer: D
Up to 12 million preschool children per year may be affected by lead in the United States. Lead is ingested from paint, soil, dust, drinking water, and in the past from gasoline. Lead poisoning is primarily a chronic condition, not acute.
Can be absorbed by inhalation, from the skin, or from the GI tract (increased by deficiencies of zinc, iron, and calcium)
Is primarily excreted through urine (80–90%), with the remainder through stool
Adults: abdominal pain, anemia, renal disease, azotemia, neurologic manifestations such as headache and memory loss; possible hypertension
Chronic: irreversible neurologic damage such as mental retardation and poor cognitive/behavioral function
Blood lead level is the key to diagnosis, with <10 µg/dL considered acceptable. In children, “lead lines” are densities seen at the metaphyseal plate of the long bones, indicating long-term exposure.
Treatment. Treatment includes chelation with calcium EDTA, dimercaprol (BAL), penicilla- mine, or succimer (oral therapy). Urine output should be maintained at 1–2 mL/kg/hr to aid in maximal excretion.
Management of lead toxicity/poisoning should be done according to blood lead level:
Mild (5−44 mcg/dL): no treatment needed; repeat level in 1 month
Moderate (45−69 mcg/dL): 2,3 dimercaptosuccinic acid (DMSA)
Severe (≥70 mcg/dL): DMSA + EDTA (calcium disodium edetate)
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
384
Chapter 10 ● Emergency Medicine
LITHIUM
Lithium is a commonly used medication for the treatment of bipolar disorder and acute mania. Although effective, it has a narrow therapeutic window and is associated with toxicity. There are 2 main types:
In acute poisoning, patients do not have a lithium burden
Symptoms are primarily GI, with nausea, vomiting, cramping, and possible diarrhea
Progression can involve neuromuscular signs: tremulousness, dystonia, hyperre- flexia, and ataxia
Most common electrocardiographic finding is T-wave flattening
In chronic poisoning, patients have a large body burden of lithium
ACE inhibitors which reduce glomerular filtration rate (GFR) and enhance the tubular reabsorption of lithium
NSAIDs which reduce the GFR and interrupt renal prostaglandin synthesis
Systemic effects include renal toxicity:
Impaired sodium and water absorption, caused by inhibition of action of antidiuretic hormone on distal renal tubule
Renal tubular acidosis, chronic tubulointerstitial nephritis, and nephrotic syndrome
The most common endocrine disorder secondary to chronic toxicity is hypothyroidism. Lithium is taken up by thyroid cells and blocks thyroid hormone release from thyroglobulin, which inhibits adenylate cyclase and prevents TSH from activating thyroid cells via the TSH receptor. Acute exposure to lithium can cause leukocytosis, whereas chronic exposure can produce aplastic anemia.
Elevated lithium in the blood will confirm toxicity, although levels may not correlate with clinical symptoms. Serial levels may be warranted in cases of sustained-release tablets.
Treatment. Supportive therapy is the mainstay of treatment. Gastric lavage may be attempted if patient presents within 1 hour of ingestion.
Airway protection is crucial due to emesis and risk of aspiration.
Seizures can be controlled with BZDs, phenobarbital, or propofol.
Fluid therapy is crucial to restore GFR, normalize urine output, and enhance lithium clearance.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
385
USMLE Step 2 l Internal Medicine
Lithium is readily dialyzed because of water solubility, low volume of distribution, and lack of protein binding. Thus, hemodialysis is indicated for patients who have renal failure (and unable to eliminate lithium) and patients who cannot tolerate hydration (e.g., those with CHF, liver disease, or severe toxicity meaning neurologic symptoms >4 m/Eq/L).
Lithium is a monovalent cation that does not bind to charcoal, so activated charcoal has no role.
SALICYLATES
An elderly woman with osteoarthritis comes to the emergency department with dyspnea, intractable nausea, vomiting, and tinnitus. She is fully alert and able to give a good history. Her only other problem is hypertension. She is on a wide variety of medications to reduce her pain. Her husband says she was in so much pain lately that she took half a bottle of extra pills 30 minutes ago.
386
Salicylate intoxication results from the ingestion of a large amount of aspirin and other salicylate-containing medications, resulting in a complex, systemic toxicity.
Salicylates are complex metabolic poisons. The most common presentation is GI distress such as nausea, vomiting, and gastritis. Tinnitus is one of the more specific complaints and is one of the best ways to identify the case, so as to answer the question: “Which of the following is the most likely diagnosis?”
Salicylates affect respiratory function in 2 ways:
Directly stimulate the respiratory centers in the brainstem to cause a centrally mediated hyperventilation and hyperpnea
Are directly toxic to the lungs themselves and can cause a noncardiogenic pulmonary edema similar to ARDS
Hyperthermia is possible. CNS toxicity such as confusion, coma, seizures, and encephalopathy can also occur, with possible death.
Salicylates also interfere with Krebs cycle and lead to a metabolic acidosis through the rever- sion to anaerobic glycolysis as a method of energy production in the body. In other words, salicylates lead to significant lactic acid production with metabolic acidosis and elevated anion gap. This ultimately results in a compensatory respiratory alkalosis.
The most specific test for diagnosis is aspirin level.
Suggestive findings are elevated anion gap with metabolic acidosis. However, respiratory alkalosis may be the predominant defect, especially in early stages. Thus, blood gas can show low, high, or normal pH.
Elevated prothrombin time and hypoglycemia may occur.
Chest x-ray may be normal or show pulmonary edema.
Treatment. If the patient comes within 1 hour post-ingestion, attempt gastric decontamina- tion. Charcoal may be useful, as it is in many types of ingestion. The mainstay of therapy, however, is increasing urinary excretion by alkalinizing the urine and administering aggres- sive fluid resuscitation. When urinary pH rises, that will charge the salicylate molecule (a weak acid) and will block the reabsorption of the substance at the kidney tubule.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
Chapter 10 ● Emergency Medicine
Dialysis is sometimes necessary. Indications for dialysis include:
Renal failure
CHF
ARDS
Persistent CNS symptoms (confusion/seizures)
Hemodynamic instability
Severe acid/base or electrolyte imbalance
Hepatic failure with coagulopathy
Salicylate level >100 mg/dL
DIGOXIN
Toxicity of digoxin is seen with suicide attempts and accidental therapeutic overdosage. Toxicity is more common with renal failure because 60% of digoxin is normally excreted renally, and it will accumulate. The most common precipitating cause of digitalis toxicity is the reduction of potassium stores, often seen in patients with heart failure due to diuretic therapy or secondary hyperaldosteronism. Hypokalemia predisposes to toxicity because potassium and digoxin bind to the same site on the sodium–potassium ATPase pump, leading to increased intracellular calcium, thus leading to increased cardiac contractility. Drugs that have been implicated in digoxin toxicity include amiodarone, beta blockers, diltiazem, cyclosporine, macrolide antibiotics, indomethacin, spironolactone, and furosemide.
Clinical Presentation. GI symptoms are most common: nausea, vomiting, diarrhea, and anorexia. Neurologic and visual symptoms include blurred vision, color vision abnormality, hallucinations, and confusion. Cardiac disturbance is predominantly secondary to arrhythmia.
EKG abnormalities are common. Bradycardia, premature contractions, ventricular tachycardia, and any other arrhythmia may be seen (paroxysmal atrial tachycardia is most common).
Hyperkalemia occurs acutely from inhibition of Na+/K+ ATPase by digoxin. Order a serum
digoxin level if you suspect toxicity (due to history, etc.).
Treatment. For GI decontamination, give repeated doses of charcoal. For electrolyte abnormali- ty correction, correct the potassium.
Digoxin-specific antibodies (Digibind®) are useful for life-threatening toxicity, particularly with arrhythmias.
Use antiarrhythmics such as phenytoin and lidocaine as needed with ventricular arrhythmias.
Pacemaker placement may be necessary for bradycardia or third-degree AV block refractory to atropine.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
387
USMLE Step 2 l Internal Medicine
TRICYCLIC ANTIDEPRESSANTS
A 28-year-old man with a history of depression comes to the emergency department 1 hour after a suicide attempt with his tricyclic antidepressants and benzodiazepines. He is stuporous with respiratory rate 7/min. EKG shows a wide QRS. What is the next step?
Tricyclic antidepressants (TCAs) are characterized by a number of anticholinergic and sodium channel blocker side effects. This is the predominant cause of their cardiac and CNS toxicity.
Clinical Presentation. The most common adverse effects are anticholinergic-mediated findings of dry mouth, tachycardia, dilated pupils, and flushed skin. A quick onset with rapid deterioration is common. The most serious effects are cardiac dysrhythmia with widening of the QRS complex, resulting in ventricular tachycardia and first-degree conduction blocks.
CNS effects include altered mental status, confusion, and seizure.
Serum drug levels are the most specific test for diagnosis, but EKG with abnormalities is more important to determine who will have serious toxicity. The EKG may be normal or show any range of ventricular or atrial arrhythmias or conduction delays.
Treatment. TCA overdose has anticholinergic side effects, which include impaired peristalsis and delayed gastric emptying. TCAs block sodium channels and can cause ventricular tachycardia.
Bicarbonate protects the heart from the TCAs. Administer bicarbonate immedi- ately if QRS >100 msec. Bicarbonate is not to increase urinary excretion (as opposed to the treatment of aspirin overdose).
A 65-year-old man is brought to the emergency department by his wife with lethargy and confusion. She says that he has had a cold and has taken over-the- counter cold preparations for the last few days. On examination he is confused and does not recognize his wife. His temperature is 39.2° C (102.5° F), pulse 130/min and blood pressure 100/60 mm Hg. The skin is flushed, dry, and warm. The eyes are dilated.
Anticholinergic overdose may occur in any age group with high dose, but most commonly presents in the elderly. Anticholinergic drugs competitively inhibit binding of the neurotransmitter acetyl- choline to muscarinic acetylcholine receptors, and are commonly called “antimuscarinic agents.” Muscarinic receptors are found on peripheral postganglionic cholinergic nerves in smooth muscle (intestinal, bronchial, and cardiac), in secretory glands (salivary and sweat), on the ciliary body of the eye, and in the central nervous system. Anticholinergic agents do not antagonize the effects at nicotinic acetylcholine receptors, such as at the neuro-muscular junction.
The onset of anticholinergic toxicity varies depending on the particular toxin, but usually occurs within 1–2 hours of oral ingestion. Some drugs may take up to 12 hours to have an effect. Be aware with patients on psychotropic agents.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
388
Chapter 10 ● Emergency Medicine
The following medications may cause anticholinergic effects:
Diphenhydramine
Scopolamine and hyoscyamine
TCAs
Cyclobenzaprine
Benztropine
Belladonna
Clinical Presentation. Patients will present with the following characteristics:
“Red as a beet”: flushed, red skin due to cutaneous vasodilation
“Dry as a bone”: dry skin (anhydrosis) due to inability to sweat
“Mad as a hatter”: delirium, psychosis, hallucinations, and seizures
“Full as a flask”: urinary retention and absent bowel sounds
Tachycardia
Treatment. Treat with the ABCs, supportive care, and EKG monitoring. Anticholinergic poisoning may cause prolonged QRS and QT intervals; if that happens, use sodium bicarbonate to stabilize the myocyte membrane and prevent ventricular tachycardia. If a patient develops seizures, treat with benzodiazepines, not with phenytoin or fosphenytoin.
Organophosphates inhibit cholinesterase and have muscarinic and nicotinic effects. Patients tend to be farmers and gardeners.
Nicotinic effects: weakness and decreased respiratory drive
Muscarinic effects: defecation; urinary incontinence; muscle weakness/miosis; bra- dycardia/bronchospasm; emesis; lacrimation; salivation; seizure (known as DUMB- ELSS syndrome)
To diagnose, check RBC cholinesterase levels. Do not delay treatment while waiting for results.
Treatment. The first step is for the physician to put on protective clothing, as organophos- phates are absorbed by the skin. Then, have patient remove clothing immediately. Start atropine immediately to treat the bradycardia. Start pralidoxime (2-PAM), which restores cholinesterase activity and reverses both the nicotinic and muscarinic effects.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
389
USMLE Step 2 l Internal Medicine
Note
The diagnosis of all alcohol withdrawal–related syndromes is made clinically, not by lab values.
ALCOHOL
A 35-year-old man is brought to the emergency department by his wife after he had a seizure. He is agitated and combative. He is yelling and trying to hit the nurses, and tells you that he is in France. He is also yelling at his mother, who is not in the room. His wife tells you that he drinks a liter of whiskey a day, though he has not had any in the last few days because he didn’t have the money. His pulse is 130/min, blood pressure 160/90 mm Hg, and respirations 24/min. He is diaphoretic and extremely irritable. His temperature is 38° C (100.4° F). The rest of the exam is unremarkable.
Alcoholics may present with any one of the following symptoms:
Mild withdrawal: tremors, tachycardia, anxiety; seizures may be seen 6–12 hours after last drink
Delirium tremens (DT) (manifests 48–72 hours after last drink but can last up to 10 days): mental confusion, autonomic hyperactivity, visual hallucinations, severe agitation, diaphoresis
Alcoholic hallucinosis (may be confused with DT) (starts 12–24 hours after last drink but can last days to weeks)
Wernicke encephalopathy: confusion, ataxia, and ophthalmoplegia (nystagmus)
Korsakoff psychosis: amnesia and confabulations
Treatment. Alcohol withdrawal has a very high mortality rate (5%). Benzodiazepines can be life-saving (taper dose slowly). Diazepam and chlordiazepoxide are common, due to their long half-life. Hydrate with isotonic fluids and electrolyte replacement.
Anticonvulsants have no role.
Avoid antipsychotics such as haloperidol, as they can lower the seizure threshold and cause prolonged QT interval.
Symptom-triggered therapy is recommended. A work-up for alternative diagnosis is also very important.
Use only lorazepam or oxazepam for cirrhosis
CT head to look for intracranial bleed
Lumbar puncture to rule out meningitis if there is a fever
Chest x-ray: look for aspiration pneumonia
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
390
Chapter 10 ● Emergency Medicine
High doses of thiamine IV for Wernicke and Korsakoff. Treatment for alcoholic hallucinosis is benzodiazepines and haloperidol (there is no risk of seizures, so it can be used here)
Can use barbiturates
Clinical Recall
A 17-year-old woman who drank from her grandfather’s whiskey bottle is brought to the emergency room with intermittent blurring of vision and vomiting. Which of the following is the treatment of choice?
Activated charcoal
Ethanol
Fomepizole
Thiamine
HEAD TRAUMA
Head trauma is any degree of traumatic brain injury resulting in a range of injuries, from scalp laceration to headache to loss of consciousness or focal neurologic deficits. The term does not imply a specific mechanism of injury. The injury can result in concussion, contusion, epidural hematoma, subdural hematoma, or traumatic subarachnoid hemorrhage. Cerebral contusion can progress to intraparenchymal hemorrhage.
Clinical presentation is often only suggestive of the degree of injury. The specific injury can only be determined with CT scan.
All forms of head trauma can result in headache, amnesia, and loss of consciousness. The degree of amnesia is loosely associated with the degree of head trauma, i.e., the worse the trauma, the more memory one loses.
Memory loss starts from the time of injury and stretches both forward (anterograde, in which one doesn’t remember events since the time of the injury) and backward (ret- rograde, in which one forgets past events).
Retrograde amnesia (more common) starts from the time of the injury and moves further back in time depending on the severity of the injury. The more severe the injury, the further back in time you forget.
Recovery of memory starts with recollection of the most distant progressing to the most recent memories.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
391
USMLE Step 2 l Internal Medicine
Loss of consciousness, although possible in any form of head trauma, is not always present, even with relatively severe forms of brain injury. There can be very severe intracranial bleeding (e.g., subdural hematoma) without a loss of consciousness. This is particularly true of chronic subdural hematoma.
Concussion is generally not associated with focal neurologic findings, such as motor or sensory deficits. The presence of focal findings, starting in order of highest fre- quency, is most commonly associated with epidural and subdural hematomas and contusion.
Diagnosis. CT scan of the head is the mainstay of diagnosis of brain injury. Contrast enhancement is not necessary because blood does not enhance with contrast.
Hemorrhage should be visible instantly if present at the time of the initial presentation.
Subdural hematoma is crescent-shaped and epidural hematoma is lens-shaped.
Normal x-ray does not exclude hemorrhage, and abnormal x-ray does not confirm the presence of a hemorrhage.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
392
Chapter 10 ● Emergency Medicine
wyomingbrain.com
Figure 10-15. Subdural Hematoma
(venous in origin; may be acute or chronic and may or may not result in midline shift)
wyomingbrain.com
Figure 10-17. Depressed Skull Fracture
Figure 10-16. Epidural Hematoma
(usually arterial and associated with skull fractures)
wyomingbrain.com
Figure 10-18. Cerebral Contusion
(petechial hemorrhage and/or edema, which may worsen over days)
Note
A concussion is diagnosed by a history of loss of consciousness plus a negative CT scan of the head.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
393
USMLE Step 2 l Internal Medicine
Figure 10-19. CT Scan Demonstrating Subdural Hematoma with a Midline Shift
Treatment. Severe intracranial hemorrhage should be managed by lowering the intracranial pressure.
For acute response, use hyperventilation to PCO2 of 30–35, which will cause vasocon- striction of cerebral vessels and then a drop in intracranial pressure; use in modera- tion and for limited amount of time
Osmotic diuretics such as mannitol and elevation of the head of the bed are also helpful for lowering intracranial pressure. This is in preparation for surgical evacua- tion. Elevate the head of the bed to 30 degrees and maintain systolic BP to 110–160 mm Hg. This slight degree of hypertension assures that the cerebral perfusion pressure is adequate.
Cerebral perfusion pressure is best when mean arterial pressure ≥60 mm Hg above the intracranial pressure. Stress ulcer prophylaxis with PPI is used after all severe head trauma and after intubation.
SUBARACHNOID HEMORRHAGE
A 52-year-old woman is at her job in the office when she develops the sudden onset of a severe headache, stiff neck, photophobia, and loss of consciousness. She awakens within the hour that she arrived in the hospital. She is noted to have a severe headache, nuchal rigidity, photophobia, and a temperature of 38.5 C (101.3 F).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
394
Chapter 10 ● Emergency Medicine
Subarachnoid hemorrhage (SAH) is the sudden onset of bleeding into the subarachnoid space. It most often occurs spontaneously.
Aneurysm formation is the most common etiology. The aneurysms can be saccular or fusiform, and are most commonly around the circle of Willis. The most common sites are anterior communicating artery, middle cerebral artery, and posterior communi- cating artery.
There is an association with polycystic kidney disease, Ehlers-Danlos syndrome, and some other connective tissue diseases.
Head trauma is rarely a cause.
Clinical Presentation. Sudden onset of severe headache is the hallmark of SAH. Other fea- tures include:
Loss of consciousness due to sudden rise in intracranial pressure (up to 50% of patients)
Focal neurologic symptoms (>30%), most commonly from compression of the occulo- motor cranial nerve
Other possible neurologic defects, due to the pressure of the bleed dissecting into surrounding tissues
Nuchal rigidity, photophobia, headache, and papilledema due to meningeal irritation
Fever 3–4 days after the initial hemorrhage; this can simulate meningitis because SAH is a form of chemical meningitis from irritation by the blood
Seizures (extremely common); 1-year mortality can be up to 50%, with half of the patients dying upon immediate occurrence of the bleed
Copyright 2007 Gold Standard Multimedia Inc.
Figure 10-20. Subarachnoid Hemorrhage on CT Scan
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
395
USMLE Step 2 l Internal Medicine
Note
A spinal headache may occur after a lumbar puncture in some patients. This is treated with a blood patch.
Clinical Pearl Traumatic lumbar puncture may cause RBC in the CSF,
but xanthochromia is absent.
Longer-term manifestations include the development of focal deficits, seizures, rebleeding, and hydrocephalus. Vasospasm after the bleed results in hypoperfusion to portions of the brain parenchyma and the development of stroke. Rebleeding occurs when the clot falls off of the original site of bleeding. Up to half of the people who rebleed will die. Hydrocephalus occurs when the blood cells clog up the arachnoid granulations through which CSF normally drains.
Diagnosis. The initial test is the CT scan, which is more sensitive than MRI for the diagnosis of SAH. The CT, done without contrast, has a sensitivity of 90–95% within the first 24 hours after the onset of the bleed. The diagnostic sensitivity of the CT scan actually diminishes with time as the red cells within the CSF hemolyze and are resorbed and converted into the yellow- ish coloring described on CSF examination as xanthochromia.
If the initial CT is normal and SAH is still suspected, do a lumbar puncture. The lumbar puncture is the most sensitive diagnostic test, i.e., an absence of red cells and xanthochromia on lumbar puncture essentially excludes an SAH. Xanthochromia is due to lysis of RBCs and formation of bilirubin (straw-colored CSF). Xanthochromia needs 4–6 hours to develop.
Angiography is used to determine the specific anatomic site of the vascular defect and the site of the bleed. EKG abnormalities such as inverted or enlarged T-waves are often associated with the development of SAH, and are not a cause for alarm.
Treatment. Initial steps are to maintain systolic BP at 110–160 mm Hg. Pressure higher than that can provoke more bleeding, while pressure lower can provoke cerebral ischemia through hypoperfusion (given the increased intracranial pressure). Seizure prophylaxis is not necessary.
Use nimodipine, a calcium-channel antagonist, to lower the risk of spasm in the blood vessel, thus lowering the risk of subsequent stroke.
Do angiography to determine the anatomic site that will need catheter or surgical correction. It is important to perform this so that surgical correction (usually with embolization or clipping of the AVM) can occur before rebleeding develops. If hydrocephalus occurs, then shunting will be needed. Embolization is superior to surgical clipping.
A 32-year-old fireman is caught in a fire and briefly trapped under a burning staircase. He is quickly extracted and brought to the emergency department. His respiratory rate is 14/min. He is fully alert and weighs 220 pounds. There is soot in his mouth and nose and on his face, and his sputum not carbonaceous. The nasal hairs are singed. He has no stridor or hoarseness, and the lungs are clear to auscultation. He has first-degree burns on his right leg and second- and third- degree burns on his right arm and chest.
Injuries due to burns can be divided into several types. The most common causes of death from fires are smoke inhalation and carbon monoxide poisoning. Thermal injury is most dangerous when it is respiratory related. Skin injury is labeled first degree when the skin is fully intact, even though it may be discolored.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
396
Chapter 10 ● Emergency Medicine
First-degree burns are not associated with blister formation and appear “sunburn- like.” The skin may be red or gray, but capillary refill remains normal.
Second-degree burns result in blister formation.
Third-degree burns are deeper and destroy skin appendages such as sweat glands, hair follicles, and sometimes pain receptors. This leaves patients with third-degree burns insensate; any pain they perceive is from surrounding structures where pain receptors are intact.
Although not apparent at first, respiratory injury can be the most life-threatening injury.
Soot in the mouth or nose, stridor, wheezing, altered mental status, burned nasal hairs, and burns involving closed spaces are all clues to impending pulmonary and laryngeal edema.
Shock occurs not only from direct skin loss but also from release of a host of media- tors that cause diffuse capillary leak for the first 18–24 hours. Serious capillary leak occurs when the percentage of serious body surface area burn >20–25%.
Clinical Presentation. Altered mental status, dyspnea, headache, and chest pain are clues to severe carbon monoxide poisoning. Laryngeal edema can result in stridor, hoarseness, and dyspnea. Soot in the nose and mouth can imply impending airway compromise.
The “Rule of Nines” is used to determine the body surface area that has been burned, and thus assess fluid resuscitation needs:
Patchy burns can be estimated by using one hand’s width as an estimate of 1% of body surface area burned.
Circumferential burns are critical in the assessment because as they heal, they tighten and cut off circulation, leading to limb compromise and the need for escharotomy.
Diagnosis. Besides the obvious burn, carboxyhemoglobin levels are essential in severe burns. Severe burns are defined as combined second- and third-degree burns >20% in adults or >10% in the very old or very young or third-degree burns >5% of body surface area (BSA). Chest x-ray and bronchoscopy help determine the exact extent of respiratory injury when it is uncertain.
Bronchoscopy can reveal severe thermal injury to the lungs even when the initial chest film is normal. Foley catheter placement helps determine the adequacy of fluid resuscitation.
Treatment.
If patient has signs of severe respiratory injury, the first step is to intubate before more severe laryngeal edema can occur and make the intubation difficult.
If carboxyhemoglobin level is significantly elevated (>5–10%), administer 100% oxygen.
Fluid resuscitation over the first 24 hours is based on a formula of 4 mL per % BSA burned per kg. Use second- and third- degree burns in your calculation.
Use Ringer’s lactate as the preferred fluid; give 50% of the fluid in the first 8 hours, 25% in the second 8 hours, and 25% in the final 8 hours. (This is known as the Parkland formula.)
Afterward, when the diffuse capillary leak improves, give enough fluid to maintain urine output >0.5–1 mL per kg per hour.
Note
The Rule of Nines differs between adults and children. Refer to Pediatrics for more information on the treatment and calculation of burns in children.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
397
USMLE Step 2 l Internal Medicine
Give stress ulcer prophylaxis with H2 blocker or PPI.
To prevent infection, use topical treatment with silver sulfadiazine.
Do not break blisters and do not use steroids.
Escharotomy is useful in circumferential burns.
Skin grafting is done on the basis of the size and severity of the injury.
Patients with burn injuries are at increased risk for pseudomonal and staphylococcal infections; if there is concern for infection, give IV antibiotics that cover these organisms.
Heat Disorders
Heat disorders are divided into 2 main groups: exertional and nonexertional. Exertional disor- ders vary from mild heat cramps to more severe heat exhaustion to potentially lethal heat stroke. Nonexertional disorders are malignant hyperthermia and neuroleptic malignant syndrome.
Heat Cramps. This is a mild exertional disorder that can happen to any healthy person who develops fluid and electrolyte depletion.
Heat Exhaustion. This is a more severe exertional heat disorder.
Patient is weaker with more systemic symptoms. Body temperature may be slightly elevated.
Patient is able to sweat and remove heat from the body. There may be mild neuro- logic symptoms such as headache, nausea, and anxiety, but severe confusion is rare.
Death is very unlikely, but the disorder can progress to heat stroke if not treated.
Heat Stroke. This is a very severe and potentially life-threatening disorder.
Patient has lost the ability to remove heat from the body because of an impaired ability to sweat; 50% of patients retain some capacity to sweat but in insufficient amounts to keep up with heat generation.
Body temperature may become severely elevated (>41° C), resulting in confusion, disorientation, nausea, blurred vision, and seizures.
Numerous lab abnormalities may occur, including hemoconcentration, rhabdomy- olysis, and elevated BUN, creatinine, and white cell count.
Anuria, DIC, and lactic acidosis may develop.
Treatment for non-exertional heat stroke is IV fluid replacement and external evaporative cooling of the body (place in cool environment and spray with water, then fan to evaporate the fluid). Treatment for young athletes with exertional heat stroke is immersion in ice water. In the elderly, chlorpromazine and diazepam can be used to control shivering.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
398
Chapter 10 ● Emergency Medicine
Malignant Hyperthermia. This is a nonexertional heat disorder occurring as an idiosyncratic reaction to an anesthetic agent such as halothane or succinylcholine. Virtually any anesthetic may cause it.
Rhabdomyolysis may develop.
Treatment is dantrolene.
Neuroleptic Malignant Syndrome. This is an idiosyncratic reaction to a wide variety of phenothiazines or butyrophenones such as haloperidol.
Muscular rigidity and rhabdomyolysis may occur.
Treatment, besides stopping the drug, is bromocriptine or dantrolene.
Hypothermia
Hypothermia is the reduction of core body temperature <35° C (normal 37° C). Core tempera- ture is measured with a rectal probe or through the esophagus. It often occurs in association with alcohol intoxication, particularly in the elderly.
Severe hypothermia is core temperature <30° C.
Clinical Presentation. The most common symptoms of severe hypothermia are related to the central nervous system. Lethargy, confusion, and weakness may occur. Death is most com- monly from arrhythmia (Osborne wave or J wave). This is from the effect of the cold on altering cardiac conduction. Other complications include metabolic acidosis, respiratory acidosis, kidney injury, and hyperkalemia.
Diagnosis. The EKG can show a wide variety of serious arrhythmias, including ventricular fibrillation or ventricular tachycardia. The most characteristic finding is an elevated J-point, known as Osborne waves. J-wave elevation may mimic ST-segment elevation.
Treatment. Most patients respond well to common-sense treatment such as a warm bed, bath, or heated blanket. For very severe cases, use warmed IV fluid or humidified oxygen. Use caution, though, because overly rapid rewarming can cause arrhythmias; if life-threatening arrhythmias occur, it is important to continue resuscitative efforts until body temperature >35°
If the patient is cold but not shivering, active measures should be used:
Active external rewarming: only to truncal areas; warm blankets; heat lamps; hot-water bottles
Active internal rewarming: warm IVFs (45° C), warm humidified oxygen (45° C), warmed gastric lavage via NGT, warmed hemodialysis
Hypothermia is one of the few times in which a patient can be resuscitated from pulseless- ness beyond the usual 10 minutes of efforts.
Note
Hypothermia must be worked up for precipitant factors:
Hypoglycemia (most
common cause)
Hypothyroidism
Sepsis
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
399
USMLE Step 2 l Internal Medicine
Clinical Recall
A 65-year-old woman is brought to the emergency department after a fall in the shower. On examination, there is a contusion on the posterior aspect of the skull. On examination of the eye, there is mild dilation of the right pupil with evidence of papilledema in both eyes. Which of the following would not be considered in the management of this condition at this time?
Administer IV steroids
Elevate head end of bed
Hyperventilate the patient
Maintain systolic blood pressure above 110 mm HG
Answer: A
400
Ionizing radiation damages tissues primarily through destructive changes to DNA molecules. Ionizing radiation is lethal and can often cause cancer. Longer exposures give worse injury.
Nonionizing radiation is less destructive to tissue and causes injury primarily as burns. Examples include infrared, ultraviolet, and microwave radiation.
Clinical Presentation. To give a sense of scale, mortality is almost zero with <2 Gy (or Sv) of exposure. This rises almost to 100% mortality with >10 Gy (or Sv). (10 Gy = 1,000 rad.)
Any cell can be damaged by ionizing radiation, but the more rapidly the cell divides, the more vulnerable it is to radiation. This is because more DNA damage can be done during the time of division.
Common sites of radiation injury include the following:
Bone marrow: As little as 2–3 Gy (200–300 rad) can depress lymphocyte count. Neutro- phils are the next most sensitive cell, while erythrocytes are the least sensitive.
Long-term, leukemia is the earliest and most common cause of cancer from radiation exposure.
Thrombocytopenia can result in death from bleeding.
Overall, infection and bleeding from depressed bone marrow function are the most common causes of death in acute exposure.
Gonads: 2−3 grays result in temporary aspermatogenesis, while 4−5 grays can make men permanently sterile. Testes are more sensitive than ovaries.
GI: Nausea and vomiting are the most common early symptoms of radiation exposure (50% of cases with 2 Gy (200 rad) exposure and 100% of patients with >3 Gy expo- sure). Also, the rapidly reproducing intestinal lining ulcerates, leading to bleeding and infection later.
Other common sites of radiation injury: the skin, salivary glands, respiratory epithelium, and thyroid glands
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
Chapter 10 ● Emergency Medicine
Treatment. Management is supportive. There is no specific therapy to reverse radiation injury.
Antiemetics, given that nausea is such a common feature of radiation sickness
Blood products, ie, platelets and RBC transfusions; WBC transfusions do not help
Colony-stimulating factors (G-CSF, GM-CSF) to help restore marrow function
Antibiotics, used as needed when infection develops
Bone marrow transplantation (occasionally useful)
DROWNING
Drowning is a significant worldwide public health concern. It is a major cause of disability and death, particularly in children. At least 35% of survivors sustain moderate-to-severe neu- rologic sequelae.
Alcohol and drug use are strongly associated with an increased risk of death by drowning.
Muscular exhaustion, head and spinal trauma, or acute myocardial infarction are predispositions to drowning and near drowning.
10−20 percent of drowning victims may have suffered dry drowning, in that there is no water aspirated into the lungs. Dry drowning is secondary to laryngospasm.
Drowning from aspiration of water can be divided into 2 types:
Freshwater (hypotonic) alters pulmonary surfactant, resulting in unstable alveoli which then collapse.
Seawater (hypertonic) draws water out of the body into the lung, causing systemic hypovolemia and hemoconcentration.
The lungs become even more heavy and fluid-filled because the surfactant is essentially washed out.
Presentation. Only the presentation of near drowning is important to discuss because drowned victims are dead. Presentation can vary from coma to agitation. Cyanosis, coughing, and signs of pulmonary edema, such as tachypnea, tachycardia, and blood-tinged sputum are common. Rales and rhonchi can be found on the exam. Hypothermia is also common.
Laboratory Findings. Arterial blood gases show hypoxia and hypercarbia, as well as metabolic acidosis from anaerobic metabolism. Hyperkalemia may be present if there is significant hemolysis. Renal insufficiency on the basis of hypoxia is a rare finding.
Treatment. The first task is to remove the patient from the water and do ABCs (airway/ breathing/circulation) of resuscitation.
Endotracheal intubation as needed
Supplemental oxygen
Positive pressure mechanical ventilation as needed
Note
Near drowning is survival after immersion, at least for some time. Morbidity is high and death may occur later. The exact definition is still the topic of much debate.
Drowning is defined as death within 24 hours after submersion in water.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
401
USMLE Step 2 l Internal Medicine
After removal from water, the most important initial step is to establish an adequate airway. Continuous positive airway pressure (CPAP) is the most effective treatment and gives the best correction of hypoxia and acidosis. Even if the patient appears comfortable initially, observe for 24 hours because ARDS (acute respiratory distress syndrome) may develop as a late finding.
The following treatments do not help and may be harmful:
Abdominal thrusts may lead to aspiration of gastric contents.
Antibiotics are indicated only if pneumonia develops.
Steroids have no benefit.
ANAPHYLAXIS
Anaphylaxis is a syndrome of histaminergic release in which there are signs of severe injury such as urticaria, angioedema, hypotension, tachycardia, and respiratory compromise. As an idiosyncratic reaction, patients can develop anaphylaxis from any medication, food, insect bite, or antigenic substance entering the body by oral or parenteral route.
Penicillin, phenytoin, contrast agents, and allopurinol allergy are common
Clinical Presentation. Mild symptoms include a rash known as “hives.” More severe symp- toms include dyspnea, stridor, tachycardia, hypotension, and hemodynamic collapse.
Epinephrine injection, IV fluid, antihistamine, and systemic corticosteroids. (severe symptoms of anaphylaxis with hemodynamic instability)
Cat and Dog Bites
Dog bites (most common bites in United States) are usually ripping and tearing in nature, whereas cat bites are usually a puncture wound.
Clinical Presentation. Infection is more likely in patients with a delay in treatment, extremes of age and extremity injuries. Infections are most often polymicrobial.
Cat bites are highly associated with Pasteurella multocida.
Dog bites are associated with Pasteurella, Eikenella, hemolytic streptococci, Staph aureus, and Capnocytophaga canimorsus.
Treatment. Treatment is exploration, debridement, irrigation, and proper wound care. If prophylactic antibiotics are indicated, the drug of choice is amoxicillin and clavulanate (with penicillin-allergy, use a combination of clindamycin or metronidazole plus ciprofloxacin or trimethoprim/sulfamethoxazole or doxycycline).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
402
Chapter 10 ● Emergency Medicine
Indications for antibiotic prophylaxis:
Any cat bite
Any bite on hand, face, joint, or genitals
Immunocompromised status
Asplenic patient (high risk of overwhelming sepsis from Capnocytophaga canimorsus)
Most wounds should be left unsutured except for facial wounds for cosmetic reasons. Never suture the hand.
Human Bites
Human bites carry an infection rate of 15%, which is greater than cat and dog bites together. The most common organisms are anaerobic and aerobic bacteria, specifically, Eikenella corrodens.
Hepatitis B and HIV can also be transmitted through bites but are much less common.
Treatment. Clean and irrigate wound well. If bite <12 hours old, close loosely.
There is no place for cultures on fresh bites.
Rabies
Rabies is a viral disease that affects the central nervous system. It is carried by bats, dogs, bats, raccoons, rats, skunks, and foxes; transmission occurs through their saliva a few days before death, when the animal “sheds” the virus. Since it affects the nervous system, most rabid animals behave abnormally.
The incubation period of rabies is up to 1 year. It is nearly 100% fatal once the disease has been contracted.
Clinical Presentation. Prodrome of 2−10 days, including fever and paresthesias at the bite site. Neurologic changes include aphasia, paralysis, hypersalivation, and myoclonus. Diagnose with viral cultures from saliva, CSF, or serum.
Treatment. Ribavirin has been used in confirmed cases. Prophylaxis with human rabies immunoglobin (HR16), which gives immediate passive immunity, and human diploid cell vaccine (HDCV) should be given. The current guidelines for rabies vaccination are as follows:
Preventive vaccination (no exposure) (usually 3 doses)
Those at high risk of exposure to rabies (veterinarians, animal handlers, rabies lab workers, etc.) should be offered the vaccine
Those in frequent contact with rabies virus or potentially rabid animals (e.g., an international traveler who is likely to come into contact with animals in a region where rabies is common) should be offered the vaccine
Vaccination post-exposure
Those who have been bitten by an animal or may have been exposed to rabies should receive wound cleaning and started on vaccine
Note
All human and monkey bites should receive prophylactic antibiotics.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
403
USMLE Step 2 l Internal Medicine
If never vaccinated against rabies previously: 4 doses (1 dose right away and additional doses on days 3, 7, and 14); give rabies immune globulin at first dose
If vaccinated against rabies previously: 2 doses (1 dose right away and another on day 3); no need to give rabies immune globulin
Snakebites
Although 50,000 snakebites are reported per year worldwide, only about 8,000 are poisonous. There are <5–10 deaths per year, with rattlesnakes accounting for almost all fatalities.
Snake venom contains numerous potentially dangerous substances, such as hemolysis toxin, cardiotoxin, neurotoxin, and proteolytic enzymes. Some of these substances can result in neuromuscular blockade.
Factors which affect the severity of the bite:
Body size: The smaller the body, the worse the effect; thus, bites tend to be worse in children.
Location of bite: Trunk and face bites are worse than extremity bites.
Exercising after bite: Muscular activity helps spread the venom through the lymphatics (so minimize physical activity).
Depth of injury: No poisoning occurs in 20–50% of bites because they are too superficial.
Treatment. Transport the patient immediately to the nearest medical facility.
Immobilize: will help decrease the spread of venom through the lymphatics, which increases with muscular contraction
Apply compression bandage: will help to decrease lymph flow; be sure not to apply so tightly that it decreases venous flow
Antivenin: be cautious of anaphylactic reaction that may occur to the horse serum
Supportive: manage hypotension with fluids; ventilatory support may be necessary
Ineffective therapy includes incision and suction of the bites. Tourniquets and ice immersion do not help and might be harmful.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
404
ChaNpetuerroTloitglye
1#1
Outline the presentation, diagnosis, and management of disease of the spinal cord including spinal cord compression, syringomyelia, subacute combined degeneration, anterior spinal artery occlusion, ALS, and Brown-Sequard syndrome
Describe the epidemiology, classification, and treatment of seizures and epilepsy
Describe the presentation, diagnosis, and management of movement disorders including benign essential tremor, restless leg syndrome, Huntington disease, and Parkinson disease
Present the diagnosis and management of autoimmune neurological diseases, includ- ing Guillain-Barre syndrome, MS, and myasthenia gravis
Provide a differential diagnosis and work-up of patients presenting with headache, vertigo, or dizziness
List the criteria for prevention of cerebrovascular accident in patients with TIA, and outline the management of patients with acute cerebrovascular accident
Describe the epidemiology of dementia and typical course and complications
SPINAL CORD COMPRESSION
A 63-year-old African-American man is brought to the emergency department complaining of back pain that started gradually 3 days ago. The patient describes the pain as “band-like” around the abdomen, without radiation. His past medical history is significant for prostate cancer, diagnosed 3 years earlier, and treated with radiation.
Note
Spinal Cord Compression Acute: trauma
Subacute: neoplasm most common cause
Chronic: herniation
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
405
USMLE Step 2 l Internal Medicine
Spinal cord compression is an acute syndrome of back pain, associated with compression of the spinal cord. It is considered a neurologic emergency. Common causes include cancer (lymphoma; multiple myeloma; carcinoma of prostate, lung, breast, kidney, colon), herniated disk, epidural abscess, hematoma, and trauma (cause of acute cases).
Patients commonly present with insidious onset of mild sensory disturbance, lower extremity weakness, and/or sphincter or sexual dysfunction. The earliest symptom is almost always pain (which may be intensified by actions that increase intrathoracic and thus cerebral
spinal fluid pressure).
Diagnosis of acute spinal cord compression has to be suspected on the basis of the history and neurologic exam; that is essential for instituting appropriate therapy early in the course of the disease. Cancer, fever, or bowel/bladder incontinence/retention in the clinical history would strongly suggest the possibility of acute spinal cord compression. Also, neurologic exam will show:
Dermatomal sensory level with bilateral lower extremity weakness
Upper motor neuron signs below the level of compression
The thoracic cord is the most common site of compression (70%) because the spinal cord is narrowest at that point. Symptoms may progress quickly.
Diagnosis. Plain x-ray is abnormal in the far majority of cases. They are rarely done. The diagnos- tic test of choice is MRI of the spine; when that is contraindicated, do a CT myelogram.
Treatment. Once the diagnosis is suspected, start high-dose dexamethasone immediately. After the specific etiology is identified more clearly by MRI, initiate specific therapy:
For a radiosensitive tumor such as lymphoma or multiple myeloma, start radiation therapy as soon as possible.
For herniated disk, epidural abscess, or hematoma, start surgical decompression.
Prognosis depends mainly on the functional status of the patient at the time of presentation. Up to 80% of patients who are initially able to ambulate retain that ability after treatment. Only 5% of patients without antigravity leg strength are able to ambulate after treatment.
SYRINGOMYELIA
Syringomyelia is cavitation of the spinal cord. It occurs as communicating (with the CSF pathways) or noncommunicating. Communicating syringomyelia is usually associated with the congenital Arnold Chiari malformation. Noncommunicating syringomyelia is typically secondary to trauma or tumors of the spinal cord.
In the cervical vertebrae of both gray and white matter, there is typically sensory dissociation with impaired pain and temperature and intact sensation to light touch. The loss of pain and temperature occurs in a cape-like distribution across the neck and arms. There is sparing of tactile sensation, position, and vibratory sense. Reflexes are lost.
As the lesion enlarges, there may be lower motor neuron manifestations at the level of the lesion with upper motor neuron signs below the lesion. Cavitation most commonly occurs at the level of the cervical cord. MRI is the most accurate diagnostic test. Treatment is surgical, but often unsatisfactory.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
406
Chapter 11 ● Neurology
Note cavitation of spinal cord in shaded area
Figure 11-1. Syringomyelia
SUBACUTE COMBINED DEGENERATION
Subacute combined degeneration occurs with vitamin B12 deficiency. Patients will complain of distal paresthesias and weakness of the extremities followed by spastic paresis and ataxia. On exam there is a combined deficit of vibration and proprioception with pyramidal signs (plantar extension and hyperreflexia). Diagnosis is established by finding a low serum vitamin B12.
Treatment is vitamin B12 replacement.
ANTERIOR SPINAL ARTERY OCCLUSION
Anterior spinal artery occlusion presents with acute onset of flaccid paralysis that evolves into a spastic paresis over days to weeks. Additionally, there is loss of pain and temperature sensation with sparing of vibration and position sense as the posterior columns are supplied by the posterior spinal artery. Everything (motor, sensory, autonomic) is lost below the level of the infarction with the striking exception of retained vibration and position sense. Treatment is supportive.
Note dorsal columns remain intact
Figure 11-2. Anterior Spinal Artery Occlusion
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
407
USMLE Step 2 l Internal Medicine
BROWN-SÉQUARD SYNDROME
Hemisection of the cord results in a lesion of each of the 3 main neural systems: the principal upper motoneuron pathway of the corticospinal tract, one or both dorsal columns, and the spinothalamic tract. The hallmark of a lesion to these 3 long tracts is presentation with 2 ipsilateral signs and 1 contralateral sign.
A lesion of the corticospinal tract results in an ipsilateral spastic paresis below the level of the injury.
A lesion to the fasciculus gracilis or cuneatus results in an ipsilateral loss of joint position sense, tactile discrimination, and vibratory sensations below the lesion.
A lesion of the spinothalamic tract results in a contralateral loss of pain and tempera- ture sensation starting 1 or 2 segments below the level of the lesion.
At the level of the lesion, there will be an ipsilateral loss of all sensation, including touch modalities as well as pain and temperature, and an ipsilateral flaccid paralysis in muscles supplied by the injured spinal cord segments.
Figure 11-3. Hemisection: Brown-Séquard Syndrome
Which of the following is not a symptom of spinal cord compression?
Back pain
Visual disturbance
Sexual dysfunction
Sphincter dysfunction
Answer: C
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
408
Chapter 11 ● Neurology
CEREBROVASCULAR ACCIDENT
A 56-year-old woman is brought to the emergency department by her daughter complaining of sudden onset of right upper extremity weakness that began while she was watching television early this morning. The daughter became concerned when her mother was unable to talk in response to questions. Neurologic exam shows right upper extremity weakness with pronator drift and right facial nerve palsy. When questioned, the patient seems to understand what is being said but cannot clearly respond.
Cerebrovascular accident (CVA) is sudden onset of a focal neurologic deficit. The principal mechanisms by which stroke occurs are:
Vascular dissection
Bleeding
Clinical Presentation. Stroke should be considered in any patient who presents with acute onset of a focal neurologic deficit. The specific clinical syndrome is determined by the mecha- nism and vascular territory affected.
The blood supply to the brain is divided into 2 systems: the carotid (anterior) circulation and the vertebrobasilar (posterior) circulation. The major blood vessels comprising the anterior circulation include the anterior cerebral artery (ACA) and middle cerebral artery (MCA).
Occlusion of the ACA presents with contralateral weakness and sensory loss in the leg more than in the upper extremity. Urinary incontinence, confusion, and behavioral disturbances are common. Lower extremity weakness exceeds upper extremity weakness.
aic.cuhk.edu.hk/web8
Figure 11-4. CT Scan of a Right MCA Infarction
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
409
USMLE Step 2 l Internal Medicine
Occlusion of the MCA presents with contralateral hemiplegia, hemisensory loss, and homony- mous hemianopia with eyes deviated toward the cortical lesion. Dominant hemisphere involve- ment results in aphasia. Nondominant hemisphere involvement results in preserved speech, comprehension with confusion, and apraxia with spatial and constructional deficits.
The posterior circulation provides blood supply to the cerebellum, brain stem, occipital lobe of the cortex, and pons. The major blood vessels that comprise the posterior circulation are the posterior cerebral artery (PCA), basilar artery (BA), and vertebral arteries.
Table 11-1. Posterior Circulation Syndromes
Ipsilateral | Contralateral | |
Weber | CN III | Hemiplegia |
Benedikt | CN III | Ataxia |
Body sensory loss |
Occlusion of the PCA presents with contralateral homonymous hemianopia, visual hallucina- tions, and agnosias. Occlusion of the penetrating branches of this vessel can result in CN III palsy with contralateral hemiplegia (Weber syndrome) or CN III palsy with contralateral ataxia or athetosis (Benedikt syndrome).
Specific syndromes associated with occlusion of basilar artery branches include the “locked-in syndrome” (paramedian branches), presenting as quadriparesis with intact vertical eye movements; and Wallenberg syndrome (posterior inferior cerebellar artery), which presents as ipsilateral facial sensory loss, contralateral body sensory loss, vertigo, ataxia, dysarthria, dysphagia, and Horner syndrome.
Occlusion of the major cerebellar arteries produces vertigo, vomiting, nystagmus, and ipsilat- eral limb ataxia.
Diagnosis. The initial test of choice will always be noncontrast CT of the head, done to distinguish between hemorrhagic and ischemic stroke. Noncontrast CT is the most sensitive test for detecting blood in the brain. CT is often negative for ischemia within the first 48 hours after symptom onset; diffusion-weighted MRI is the most accurate test for detecting cerebral ischemia.
Diagnostic workup for acute ischemic stroke involves searching for embolic sources (echocar- diogram, carotid duplex, and 24-hour Holter monitor). Also consider a workup for inherited hypercoagulability. Subarachnoid hemorrhage is associated with EKG abnormalities such as ischemia or inverted T-waves, called cerebral T-waves. A “bubble study” is done on the echocar- diogram to detect the presence of a patent foramen ovale or other cardiac defect.
Treatment. Tissue plasminogen activator is given if the patient presents within 3 hours of symptom onset. Contraindications for use of tissue plasminogen activator include:
Stroke or serious head trauma within 3 months
Hemorrhage (GI or GU) within 21 days
Surgery within 14 days
History of intracranial hemorrhage
BP >185/110 mm Hg
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
410
Chapter 11 ● Neurology
Current use of anticoagulants
Platelets <100,000/mm3
Coagulopathy (PT >15 seconds)
Patients who receive tissue plasminogen activator in an appropriate manner have better neurologic function 3 months after CVA as compared with those who do not receive it.
There is no clear benefit to the use of heparin with stroke. That is because of the increased risk of bleeding. Any benefit is offset by adverse events associated with treatment. For every stroke prevented, one intracranial hemorrhage is caused.
Antiplatelet therapy is most useful in secondary prevention of ischemic stroke. Aspirin is considered first-line treatment (start 24 hours after TPA).
When there is a known allergy to aspirin or recurrent cerebrovascular events on aspirin alone, add dipyridamole or switch to clopidogrel to enhance antiplatelet therapy.
Do not combine aspirin and clopidogrel for a stroke. Combination of anti-platelet agents is used on coronary disease but not cerebral disease.
Ticlopidine is no longer used because the rates of thrombotic thrombocytopenic purpura and leukopenia are unacceptably high.
Subarachnoid hemorrhage is treated with nimodipine to reduce the risk of ischemic stroke. Early surgical intervention to clip off the aneurysm or embolize the vessel with a catheter should be done in good operative candidates. “Early” means within several days. Don’t wait for the unrepaired aneurysm to rebleed. Unruptured aneurysms found incidentally should be repaired if they exceed 10 mm in size.
Carotid endarterectomy is recommended when an occlusion exceeds 70% of the arterial lumen and the lesion is symptomatic. Endarterectomy may benefit those who are asymptomatic if there is >60% stenosis in men age <60. The benefit of endarterectomy is less certain in women because they have a lower risk of stroke. The more severe the disease, the greater the benefit.
Carotid stenting is an alternative to endarterectomy.
Endarterectomy is simply not clear in asymptomatic carotid stenosis. The Step 2 exam does not engage in unanswerable, controversial issues.
Carotid angioplasty and stenting are not as good as endarterectomy for symptomatic patients with >70% stenosis. Angioplasty and stenting should be considered only for those who cannot undergo surgical endarterectomy.
SEIZURES AND EPILEPSY
A 29-year-old man is brought to the emergency department by ambulance after being found convulsing in his bedroom. His mother says that during the episode, her son was unable to respond to her frantic cries. She describes jerking movements that became more frequent and then stopped after approximately 1 minute. The mother says that he seemed tired and lethargic for at least 20 minutes after the episode. She then called the ambulance to bring her son to the hospital.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
411
USMLE Step 2 l Internal Medicine
A seizure is a paroxysmal event due to abnormally discharging central nervous system (CNS) neurons. Epilepsy is a condition involving recurrent seizures, due to a chronic underlying pro- cess. The causes of seizure can be remembered from the acronym “VITAMINS”:
Vascular (stroke, bleed, arteriovenous malformation)
Infection (meningitis, abscess, encephalitis)
Trauma (especially penetrating)
Autoimmune (CNS vasculitis)
Metabolic (hyponatremia, hypocalcemia, hypomagnesemia, hypoglycemia, hypoxia, drug overdose/withdrawal)
Idiopathic
Neoplasm
Clinical Presentation. A seizure is essentially a paroxysmal, involuntary event (associated with abnormal movement or change of consciousness or both). Characteristically, it is sudden in onset, with or without an aura. Patients often complain of disorientation, sleepiness, and aching muscles for minutes to hours after the event. Patients may also experience inconti- nence, tongue biting, and headache as a result of the seizure.
It may be difficult to differentiate seizure from syncope, and it is important to obtain a complete history from anyone who witnessed the event. Generally, syncope will not present with signifi- cant postictal symptoms. Patients will recover consciousness within several minutes of the event. Physical exam for syncope will show no evidence of incontinence or tongue biting.
It is important to classify seizures according to their clinical features because this will deter- mine what medications will be used for treatment. Seizures can be classified as partial versus generalized, and then simple versus complex.
Partial seizure occurs within discrete portions of the brain. Symptoms include involuntary jerking of a finger or hand.
If consciousness is maintained for the duration of the seizure, that is a simple partial seizure. If there is a change in consciousness for the duration of the seizure, that is a complex partial seizure.
When a partial seizure progresses to a generalized seizure, that is a partial seizure with secondary generalization. Typically, the seizure will begin focally and become generalized as seizure activity involves both cerebral hemispheres.
Generalized seizure arises from both cerebral hemispheres spontaneously without any detectable focal onset.
Generalized tonic-clonic (grand mal) seizure is characterized by tonic contraction of muscles throughout the body followed by intermittent relaxation of various muscle groups (clonic phase).
Absence (petit mal) seizure is more common in children than adults; it is character- ized by sudden, brief loss of consciousness without loss of postural tone. Character- istically, EEG will show a generalized, symmetric 3-Hz spike-and-wave discharge pattern. Atonic seizure is characterized by sudden loss of postural tone lasting 1 to 2 seconds. Myoclonic seizure is characterized by sudden, brief muscle contraction.
Status epilepticus is defined as recurrent or continuous seizures (lasting at least 5–30 min).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
412
Chapter 11 ● Neurology
Diagnosis. For idiopathic seizure, diagnosis is made only after secondary precipitating factors have been ruled out. For epilepsy, diagnosis is done with EEG. However, an abnormal EEG alone is not diagnostic, as 2-18% of the population has an abnormal EEG. Always check serum electrolytes, glucose, toxicology, and arterial blood gas to rule out hypoxia as a cause of a patient’s seizure. CT scan or MRI of the head is usually indicated to rule out a structural lesion as the cause of seizure. Think of any seizure as a symptom, much like shortness of breath or chest pain, which has an extensive differential diagnosis. The evaluation of any seizing patient is to rule out reversible causes of seizure.
Treatment of seizure can be divided into management of the acutely seizing patient (status epilepticus) and the chronic epileptic patient.
In the acutely seizing patient:
Secure the airway, breathing, and circulation.
Once an adequate airway is established, breathing is assured, and the patient is hemodynamically stable, then simultaneously evaluate and treat any precipitating cause of seizure.
If the patient continues to seize, the following strategy is appropriate.
The initial drug of choice is lorazepam or diazepam (both benzodiazepines). These medications work by potentiating GABA receptor function.
If the patient continues to seize, add phenytoin or fosphenytoin, which inhibits sodium-dependent action potentials. CNS side effects of phenytoin include diplo- pia, dizziness, and ataxia. Systemic side effects include gum hyperplasia, lymphade- nopathy, hirsutism, and rash.
If the patient continues to seize, add phenobarbital. Side effects include sedation, ataxia, and rash.
If, despite all of the above therapy, the patient continues to seize, add midazolam or propofol.
In patients with first-time seizure, anticonvulsant therapy should be started only if patient has:
Presented with status epilepticus
Strong family history of seizure
Abnormal EEG
Otherwise, first-time seizure is generally not treated with long-term anticonvulsant therapy. There is no superior drug in pregnancy. Valproic acid is clearly more dangerous in pregnancy.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
413
USMLE Step 2 l Internal Medicine
Lorazepam
1.
Additional emergency drug therapy may not be required if seizures stop and the cause of status epilepticus is rapidly corrected
Phenytoin or fosphenytoin
Horizontal bars indicate the approximate duration of drug infusions
Seizures continuing 2.
Seizures continuing
ly to anesthesia propofol if patient lepticus while in severe systemic
Anesthesia with midazolam, propofol, or pentobarbital
0 10 20 30 40 50 60 70 80
Time (min)
Figure 11-5. Development of Status Epilepticus
For primary generalized tonic-clonic seizures, valproic acid, phenytoin, lamotrigine, carbam- azepine, or levetiracetam can be used. Lamotrigine works by decreasing glutamate release. Side effects include Stevens-Johnson syndrome. Absence seizures are treated with ethosuximide as first-line therapy. If ethosuximide is not an answer choice, valproic acid is an acceptable option. For myoclonic and atonic seizures, valproic acid is the treatment of choice. Overall, there is no single antiepileptic drug that’s truly superior to the others—valproic acid, phenyt- oin, levetiracetam and carbamazepine are all nearly equal in efficacy.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
414
Chapter 11 ● Neurology
Partial seizures, whether they are complex or simple, and whether or not they progress to secondary generalized seizures, are all treated the same. Carbamazepine and phenytoin are considered first-line therapy. Valproic acid and lamotrigine are considered acceptable alterna- tives, as is levetiracetam. It is very difficult to determine when to stop therapy. Therapy may be stopped if the patient has been free of seizures for 2–3 years. Sleep-deprivation EEG may be done first to determine if the patient is at low risk of a recurrence. A normal sleep-deprivation EEG means there is a lower likelihood of seizures.
Clinical Recall
Which of the following symptoms are seen in Wallenberg syndrome?
CN III palsy with contralateral ataxia
Facial nerve palsy, dysarthria, dysphagia, and Horner syndrome
Vertigo is a false sensation of movement, i.e., the sensation of movement in the absence of actual movement. It may be caused by Ménière disease, labyrinthitis, positional vertigo, traumatic vertigo, perilymphatic fistula, and cervical vertigo. Other causes include vascular disease of the brain stem, arteriovenous malformation, brain tumor, MS, drug overdose, and vertebrobasilar migraine.
Clinical Presentation. With the dizzy patient, the first step is to determine the nature of the patient’s complaints. “Dizziness” is a nonspecific term that provides no meaningful informa- tion about what is occurring to the patient. Simply by taking a complete history, it is possible to determine whether the patient is experiencing vertigo or presyncope.
Patients who experience vertigo will describe a sensation of movement without actually moving. They often describe their environment ‘spinning around them.’ Sensations of tilting, swaying, or falling forward or backward are all consistent with vertigo. Acutely, these episodes are commonly associated with nausea and vomiting.
Patients who complain of presyncope will describe their symptoms as “lightheadedness” or “feeling like I’m going to black out.” Associated symptoms include generalized weakness, palpitations, and shortness of breath. It is essential to differentiate vertigo from presyncope because vertigo is usually a manifestation of neurologic disease, whereas presyncope is a cardinal manifestation of cardiovascular disease.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
415
USMLE Step 2 l Internal Medicine
Once you are convinced by the history that the patient is indeed experiencing vertigo, determine whether the vertigo is secondary to peripheral or central vestibular disease (management will differ). Several points on history and physical examination will help to distinguish them.
Table 11-2. Vertigo
Central Vertigo | Peripheral Vertigo | |
Onset | Gradual | Usually sudden |
Tinnitus, hearing loss | Absent | Present |
Neighborhood signs (diplopia, cortical blindness, dysarthria, extremity weakness/numbness) | Present | Absent |
Pure, vertical, does not suppress with fixation, and multidirectional | Mixed, horizontal, suppresses with fixation, and unidirectional |
Once you have determined that the patient has peripheral vertigo, there is a wide differential diagnosis that should be considered.
Ménière disease is characterized by tinnitus, hearing loss, and episodic vertigo. Each episode lasts 1 to 8 hours. The symptoms wax and wane as the endolymphatic pressure rises and falls. The two most common causes of Ménière disease are syphilis and head trauma.
Benign paroxysmal positional vertigo is a cause of peripheral vertigo that characteristically is exacerbated by head movement or change in head position. Typically, episodes will occur in clusters that persist for several days. There will be a latency of several seconds after head movement before the onset of vertigo. The vertigo usually lasts 10 to 60 seconds.
Labyrinthitis presents with sudden onset of severe vertigo that lasts for several days with hearing loss and tinnitus. The disease frequently follows an upper respiratory tract infection.
Perilymphatic fistula is a form of peripheral vertigo related temporally to head trauma (blunt trauma to the ear, e.g., a slap to the ear) or extreme barotrauma during air flight, scuba diving, or vigorous Valsalva maneuver. Explosions deafen people.
Central vertigo is caused by any cerebellar or brain-stem tumor, bleed, or ischemia. Drug toxicity or overdoses are important causes of central vertigo. Also, in the young patient with unexplained central vertigo, consider multiple sclerosis.
Treatment. Symptomatic treatment for peripheral vertigo includes meclizine or, in severe cases, diazepam.
Ménière disease is treated with a low-salt diet and diuretics. In patients who fail medical therapy, you can consider surgical decompression.
Benign paroxysmal positional vertigo is treated with positional maneuvers that attempt to move the otolith out of the circular canals (e.g., Dix Hallpike and Barany maneuvers).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
416
Chapter 11 ● Neurology
Vertigo secondary to labyrinthitis is treated symptomatically with meclizine and diazepam when the symptoms are severe. Steroids help labyrinthitis.
DISORDERS ASSOCIATED WITH HEADACHE
Headache
A 32-year-old woman comes to the office complaining of a headache that started 2 days ago. She locates her headache at the right side of her head and describes it as throbbing in quality. The headache is worsened by walking up stairs or around the block. She experiences nausea but denies vomiting. She also states that loud noise and bright light exacerbate her pain.
Headache is defined as pain located in the head, neck, or jaw. There are many causes. Primary headache syndromes include migraine (affecting 15% of the general population), cluster, and tension headache. Secondary causes of headache include intracranial hemorrhage, brain tumor, meningitis, temporal arteritis, and glaucoma.
Clinical Presentation. The single most important question to answer with a patient presenting with a complaint of headache is whether a serious underlying cause exists for the symptoms. By taking a thorough history and performing an adequate physical examination, it is possible to make this differentiation.
• Determine whether this is the patient’s first episode of headache: a history of recurrent symptoms makes the diagnosis of a primary headache disorder more likely, while a first-time headache, especially severe and rapidly peaking, speaks strongly for serious underlying pathology.
• Headache with fever and nuchal rigidity suggests meningitis as the underlying cause. Conversely, a headache described as “the worst headache of my life” and/or “thunder- clap” at onset, and is accompanied by nuchal rigidity without fever, suggests an intracranial hemorrhage as the underlying cause.
• Patients with brain tumor will present complaining of headache that is described as a deep, dull, aching pain and disturbs sleep. A history of vomiting which precedes the onset of headache by a number of weeks, or a history of headache induced by cough- ing, lifting, or bending, is typical of posterior fossa brain tumor.
• Patients with temporal arteritis complain of a unilateral pounding headache associ- ated with visual changes, described as dull and boring with superimposed lancinating pain. Their symptoms also include polymyalgia rheumatica, jaw claudication, fever, weight loss, and scalp tenderness (difficulty combing hair or lying on a pillow). The scalp tenderness is from pain over the temporal artery. Temporal arteritis is a disorder of the elderly, e.g., age >50. Temporal arteritis gives an elevated sedimentation rate and is diagnosed with biopsy of the temporal artery. Do not wait for the biopsy results to initiate therapy with steroids.
• Patients with glaucoma will usually give a history of eye pain preceding the onset of the headache.
Note
Any patient who presents with headache and the following should be considered to have a secondary headache syndrome:
“Worst headache of my life”
Worsening symptoms over days to weeks
Abnormal neurologic exam
Fever
Vomiting preceding the headache
Headache induced by coughing, bending, lifting, or onset age >55
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
417
USMLE Step 2 l Internal Medicine
Once serious underlying pathology is excluded by history and physical examination, primary headache syndromes should be considered. The main primary headache syndromes are migraine, cluster, and tension headache.
Migraine headaches are defined as a benign and recurrent syndrome of headache, nausea/ vomiting, and other varying neurologic dysfunctions. Patients will describe the headache as pulsatile, throbbing, unilateral, and aggravated by minor movement. Other associated features include photophobia, phonophobia, and the time to maximal pain (4 to 72 hours). Migraine is a likely diagnosis when a typical trigger can be identified. Typical triggers include alcohol, certain foods (such as chocolate, various cheeses, monosodium glutamate), hunger, or irregu- lar sleep patterns.
Migraine without aura is a migraine without a preceding focal neurologic deficit.
Migraine with aura (classic migraine) is a migraine accompanied by a preceding aura that consists of motor, sensory, or visual symptoms. Focal neurologic symptoms usually occur during the headache rather than as a prodrome. The pathognomonic aura for classic migraine is the scintillating scotoma. Only 20% of migraine headaches are accompanied by an aura. Visual auras are also described as stars, sparks, and flashes of light. Migraine equivalent is defined as focal neurologic symptoms without the classic complaints of headache, nausea, and vomiting.
Complicated migraine is migraine with severe neurologic deficits which persist after the resolution of pain.
Basilar migraine is migraine associated with symptoms consistent with brain-stem involvement (vertigo, diplopia, ataxia, or dysarthria).
Tension-type headaches are described as tight, band-like headaches that occur bilaterally. Patients may also describe their headache as “vise-like,” and these headaches may be associated with tightness of the posterior neck muscles. Patients will describe their pain as one that builds slowly, and the pain may persist for several days with or without fluctuations. Movement will not generally exacerbate the headache.
Cluster headaches, common in men, begin without warning and are typically described as excruciating, unilateral, periorbital, and peaking in intensity within 5 minutes of onset. They are rarely described as pulsatile in nature. The attacks last from 30 minutes to 3 hours and occur 1–3 × day for a 4-to-8-week period. Symptoms associated with cluster headaches include rhinorrhea, reddening of the eye, lacrimation, nasal stuffiness, nausea, and sensitivity to alcohol. Horner syndrome is sometimes found. Emotion and food rarely will trigger a cluster headache.
Diagnosis. Patients with severe, sudden onset of a first-time headache accompanied by strong evidence for an underlying cause on history or physical examination should have a CT scan of the head to rule out any secondary causes.
Treatment. Always begin with an attempt to identify probable triggers for the patient and to modify lifestyle by avoiding those triggers. Most patients will require pharmacotherapy as well.
Pharmacologic treatment for migraine headaches can be divided into management of an acute episode and prophylaxis. Initially, for a mild migraine—which is defined as headache in the absence of nausea or vomiting—NSAIDs may be used.
Acutely, abortive therapy consists of sumatriptan, which acts as a serotonin receptor agonist. Dihydroergotamine is the alternative to the triptans. Ergotamine can be used in combination with caffeine. The triptans are contraindicated in patients with known cardiovascular disease,
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
418
Chapter 11 ● Neurology
uncontrolled hypertension, or pregnancy. In addition to sumatriptan, there is almotriptan, nara- triptan, zolmitriptan, and eletriptan. These medications can be given orally, intranasally, or even subcutaneously, depending on the severity of the headache. Alternatively, ergotamine can be given for acute abortive therapy. Dopamine antagonists such as metoclopramide can be given acutely as oral formulations to aid in the absorption of other abortive medications. When given parenterally, dopamine antagonists can provide relief acutely for migraine headaches.
Prophylactic treatment for migraine therapy should be initiated when patients have acute migraine headaches >3–4/month. The best prophylactic medication is a beta blocker. Proprano- lol, valproic acid, and topiramate are all considered first-line therapy for migraine prophylaxis. Verapamil and tricyclics can also be used. These medications take 2 to 6 weeks to have an effect and can be discontinued gradually over 6 months once clinical stabilization has occurred.
Methysergide is not used because of the serious side effects associated with prolonged use (valvular and retroperitoneal fibrosis). SSRIs such as sertraline and fluoxetine can also be used for prophylaxis.
Table 11-3. Migraine Therapies
Abortive | |
Triptans
Ergotamine derivatives
Opioid analgesics are not routinely recommended for the treatment of migraine headaches because of the possibility of developing addiction. They are used only in patients with severe, infrequent migraines that are unresponsive to other therapy. Other therapies for migraine headaches are acetaminophen and NSAIDs such as ibuprofen.
Treatment for tension headaches consists of relaxation. Patients should be encouraged to find activities that are relaxing for them. Initial pharmacotherapy consists of acetaminophen and NSAIDs. If the headache remains refractory to these medications, a muscle relaxant can be added to the regimen.
Cluster headaches are treated with a triptan or 100% oxygen. Prophylaxis of cluster headaches is best done with a calcium channel blocker. Prednisone and lithium are sometimes used.
Pseudotumor Cerebri
Definition. An idiopathic increase in intracranial pressure also known as benign intracranial hypertension.
Etiology. The disorder is 8 to 10 times more common in women. There is an association with obesity, chronic lung disease, Addison disease, oral contraceptives, tetracycline use, and vitamin A toxicity. Often there is no identified cause and the disorder resolves spontaneously after several months.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
419
USMLE Step 2 l Internal Medicine
Clinical Presentation. Patients present with a headache, visual disturbances such as diplopia, and sixth cranial nerve (abducens) palsy. Clinical findings include diplopia, papilledema, and enlargement of the blind spot on visual field testing. The CT and MRI are normal, and evaluation of cerebrospinal fluid is normal beyond an increase in pressure.
Treatment. Treatment consists of weight loss, removing offending agents such as oral contraceptives, and the use of diuretics such as acetazolamide or furosemide. Steroids such as prednisone may help as well. In urgent cases, repeated lumbar punctures may help. If this is not effective and the disorder does not resolve, definitive treatment can be achieved with the placement of a surgical shunt between the ventricles and the peritoneum.
Trigeminal Neuralgia
Also known as tic douloureux, trigeminal neuralgia is an idiopathic pain syndrome resulting in sudden, severe, sharp pain starting near the side of the mouth and progressing to the ear, eye, or nostril. Attacks can be triggered by touch or movement such as talking or by eating. Trigeminal neuralgia can be so severe as to be nearly incapacitating. The pain lasts for a few seconds and disappears. Despite the pain, the sensory examination will be normal. Generally, trigeminal neuralgia is felt to be secondary to compression of the trigeminal nerve root by a blood vessel. Occasionally it can be a manifestation of multiple sclerosis or a posterior fossa tumor. With the exception of multiple sclerosis or the posterior fossa tumor, all imaging and neurologic testing will be normal.
Carbamazepine is the standard of care for treatment. In those not controlled with carbamaze- pine, phenytoin, baclofen, or gabapentin can be tried. In those not responding to any form of medical therapy, surgery or radio-frequency lesioning into the affected nerve may work.
Which of the following are the characteristic features of labyrinthitis?
Sudden onset of vertigo following upper respiratory tract infection
Vertigo that occurs with changes in head position
Central vertigo following toxicity with gentamicin
Answer: C
GUILLAIN-BARRÉ SYNDROME
A 46-year-old man is brought to your office complaining of “rubbery legs.” The patient states that his symptoms began 2 days ago and that approximately 3 weeks ago, he experienced several episodes of diarrhea, which resolved spontaneously. On neurologic examination, bilateral lower-extremity weakness and a loss of reflexes are noted.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
420
Chapter 11 ● Neurology
Guillain-Barré syndrome (GBS) is an acute, often severe polyradiculopathy, whose underlying pathophysiology is an autoimmune destruction of myelin. Evidence suggests that GBS is caused by a misdirection of the immune response, where the body’s immune system attacks self-antigens mistaken for foreign antigens (molecular mimicry).
Clinical Presentation. Most patients present with rapidly developing weakness that typically begins in the lower extremities and moves upward. On physical examination the patient is noted to lack reflexes in the muscle groups affected. The progression of the symptoms will develop over hours to days, with the legs typically more affected than the arms or face. Fever, constitutional symptoms, or bladder dysfunction are rare and should raise the possibilities of alternate diagno- ses.
In addition to the motor weakness, patients will typically complain of sensory disturbances that can take the form of pain or tingling dysesthesia. Sensory changes are due to loss of large sensory fibers, producing loss of reflexes and proprioception. Autonomic instability (profuse sweating, postural hypotension, labile blood pressure, cardiac dysrhythmias) occurs in severe GBS, requiring patient treatment in an intensive care unit.
Approximately 75% of patients who present with GBS will have a history of an infection
1–3 weeks preceding the onset of symptoms. The infection is typically in the respiratory or GI systems (Campylobacter jejuni), it might be an infection with human herpesvirus, cytomegalo- virus, or Epstein-Barr. GBS occurs more frequently in patients with HIV, systemic lupus erythematous, and lymphoma.
Diagnosis. Diagnosis lies principally in recognizing the typical pattern of weakness with the absence of reflexes, fever, and constitutional symptoms. Lumbar puncture for protein and cell count is the best initial test. The characteristic finding is elevated protein without an associated rise in cell count on CSF (only seen 48 hours after the onset of symptoms). The most accurate test for diagnosis is electromyography (EMG). EMG is used to detect evidence of demyelin- ation of the peripheral nerves.
Treatment. IV immunoglobulin and plasmapheresis are equally effective treatments. There is no benefit to combination therapy. Initiate treatment as quickly as possible, as therapy becomes ineffective about 2 weeks after the onset of symptoms.
Also, it is extremely important to monitor vital capacity in patients with GBS and initiate early respiratory support to prevent death from respiratory failure.
Glucocorticoids are not effective for acute GBS.
MYASTHENIA GRAVIS
A 35-year-old woman comes to the clinic complaining of double vision that seems to worsen near the end of the day. She also complains of difficulty chewing meat and other hard foods. She notices that her symptoms improve following a good night’s sleep. On neurologic examination you note a snarling appearance when the patient is asked to smile, and a nasal tone is heard in her voice. You also note a weakness in the upper extremities when the patient is asked to clench her fist around your finger repeatedly.
Note
The only association between immunizations and GBS occurred in 1976, with the introduction of the swine influenza vaccine. More recent formulations of influenza vaccine are associated with one case of GBS per million patients immunized.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
421
USMLE Step 2 l Internal Medicine
Myasthenia gravis (MG) is a disease of the neuromuscular junction characterized by weakness and fatigability. In MG, an autoimmune process characterized by acetylcholine-receptor antibodies leads to a decreased number of active and functional acetylcholine receptors at the postsynaptic membrane.
Clinical Presentation. The major features in a patient’s history which help to diagnose MG are muscle weakness and fatigability. Initially, patients will complain of diplopia, ptosis, and difficulty swallowing. Speech may have a “mushy” or nasal quality and facial weakness may manifest as a “snarling” appearance when smiling. As the disease progresses, weakness may become generalized, involving proximal muscles in an asymmetric pattern. Deep tendon reflexes are intact. Pupillary responses are normal. There are no sensory abnormalities. Very severe disease may affect the muscles of respiration.
Eaton-Lambert myasthenic syndrome is characterized by increasing muscle strength on repetitive contraction. This syndrome is seen in association with malignancy, especially small-cell carcinoma of the lung.
Botulism may cause a myasthenic-like illness, but the pupils are usually dilated and repetitive nerve stimulation (on EMG) shows an incremental increase in muscular fiber contraction (opposite of myasthenia gravis).
Diagnosis. The best initial test for the diagnosis of MG is the acetylcholine-receptor antibody test. In generalized MG, 80–90% of patients will have a positive test. In the presence of fatigable muscle weakness, a positive antibody test is specific and virtually diagnostic. Anti- bodies are present in only 70% of those with disease limited to the eyes.
The edrophonium (Tensilon) test is sensitive but not specific for the diagnosis. Additionally, patients may experience nausea, diarrhea, fasciculations, syncope (rare), or bradycardia during the test, which are cholinergic symptoms.
Imaging studies of the chest such as x-rays and CT scan should be performed to detect a thymoma. Thymoma is found in 10–15% of patients. Thymic hyperplasia is found in 65%.
The most accurate test for the diagnosis of myasthenia gravis is electromyography (EMG). The characteristic finding is a decremental decrease in muscle fiber contraction on repetitive nerve stimulation.
Treatment. Anticholinesterase (usually pyridostigmine or neostigmine) medications are useful for the symptomatic treatment of myasthenia gravis. Pyridostigmine is longer lasting. If treatment with anticholinesterase medications is unsuccessful in providing symptomatic relief, the physician should consider immunosuppressive therapy.
There are numerous medications used for immunosuppressive therapy. These interventions primarily differ in the onset of therapeutic benefit. They are used if thymectomy is not effective.
Glucocorticoids are effective in improving weakness but take 1 to 3 months for you to observe a clinical benefit. Steroids are the initial immunosuppressive of choice. If patients fail steroid therapy, azathioprine is the most widely used medication used in combination with steroids. The benefits of azathioprine therapy may take >3–6 months to peak. Cyclosporine and cyclophosphamide are alternatives to azathiaprine but are more toxic.
Plasmapheresis and IV immunoglobulin are immunosuppressive therapies noted for their ability to rapidly improve weakness in myasthenia gravis. They are therefore reserved for patients in acute myasthenic crisis. These therapies are used when respiratory involvement occurs or when patients go to the operating room.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
422
Chapter 11 ● Neurology
Thymectomy is indicated in postpubertal patients and in those age <60 with generalized myasthenia gravis before initiation of immunosuppressive therapy. Thymectomy is performed in those not controlled with anticholinesterase medications to prevent the use of potentially toxic medication such as systemic steroids. Thymectomies are also performed when a thy- moma is present to prevent the spread of malignant thymic disease.
Aminoglycoside antibiotics may exacerbate myasthenia gravis and should be avoided. In fact, many medications may worse myasthenia gravis.
Mycophenolate is a newer immunosuppressive drug with less adverse effects than steroids or cyclophosphamide.
AMYOTROPHIC LATERAL SCLEROSIS
Amyotrophic lateral sclerosis (ALS) is an idiopathic disorder of both upper and lower motor neurons. ALS has a unique presentation of muscle weakness combined with signs of upper motor neuron loss, cranial nerve palsies, respiratory involvement, and lower motor neuron destruction, while at the same time preserving bowel, bladder sensory, cognitive, and sexual function.
• The cranial nerve, or bulbar, palsies result in dysphagia, difficulty chewing, decreased gag reflex, dysarthria (difficulty in articulating words), and difficulty in handling saliva.
• Since there is often respiratory muscle involvement, recurrent aspiration pneumonia is the most common cause of death.
• A weak cough is also characteristic, and this only worsens the respiratory problem.
• There is no pain from abnormal sensory neuropathy because this is entirely a motor neuron disease. On the other hand, the upper motor neuron involvement gives significant spasticity that can lead to pain.
• Mentation, bowel, bladder, and sexual function remain intact for the same reason. In other words, a fully mentally alert patient loses nearly all motor control while still being able to think and perceive. The patient becomes fully aware of being trapped in a body that does not function.
• Head ptosis occurs because the extensor muscles of the neck become too weak to keep the head up.
Upper motor neuron manifestations are weakness with spasticity and hyperreflexia. Lower motor neuron manifestations are weakness with muscle wasting, atrophy, and fasciculations; this includes tongue atrophy. The combination of upper and lower motor neuron weakness is the unique presentation of ALS. The most accurate confirmatory test is the electromyogram, which will show diffuse axonal disease. CPK levels are sometimes mildly elevated, and the cerebrospinal fluid and MRI scans are normal.
The only treatment that may slow down the progression of the disease is riluzole, which is thought to work by inhibiting glutamate release. Death typically results in 3–5 years. Spasticity is treated with baclofen and tizanidine.
Many of the USMLE exam questions regarding ALS will be ethical questions on issues of the withholding of care. Since ALS has no impact on cognitive function, the patient is felt to retain the capacity to make medical decisions.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
423
USMLE Step 2 l Internal Medicine
The patient has the right to refuse potentially life-saving therapy such as antibiotics, nasogastric tube placement, tracheostomy, or mechanical ventilation.
The patient should not be allowed to commit suicide nor should the physician assist with suicide. (Withholding intubation or antibiotics is not considered assisting a suicide.)
Every adult patient with the capacity to understand the implications of his or her choice is allowed to refuse any unwanted therapy.
MULTIPLE SCLEROSIS
A 32-year-old woman comes to the emergency department complaining of numbness and tingling in her right hand. Her symptoms began several days ago and have worsened over the last several hours. She states that 3 years ago she had an episode of “seeing double” that lasted 2 days and resolved on its own. Physical examination is significant for hyperreactive reflexes bilaterally in her lower extremities. Increased spasticity is also noted in her lower extremities.
424
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS white matter characterized by a relapsing or progressive course. The cause is thought to be multifactorial; there is evidence that genetic susceptibility plays an important role. The disease occurs primarily in female populations of Northern European descent and of child-bearing age, respectively. This implies a role for some sort of environmental trigger (infectious, dietary, climatic). Pathologically, focal areas of demyelination are characteristic of the disease.
Clinical Presentation. Commonly, patients will present complaining of weakness, numbness, tingling, or unsteadiness of a limb. Urinary urgency or retention, blurry vision, and double vision are all common initial manifestations of the disease. Symptoms may persist for several weeks or may resolve spontaneously over a few days.
There are several forms of the disease that may change the course of management and are therefore important to recognize. Most patients will have a months-long to years-long disease- free period after their first exacerbation.
Relapsing remitting disease: progression is characterized by relapses of active disease with incomplete recovery during the periods of remission
Secondary progressive disease: progression becomes more aggressive so that a consistent worsening of function occurs
Primary progressive disease: symptoms are progressive from the onset of disease with the early onset of disability (least common form)
It is important to understand when the diagnosis of multiple sclerosis should be suspected. Classically, the diagnosis is made clinically when a young patient (usually age <55) presents with a history of multiple neurologic complaints that cannot be explained by the presence of one CNS lesion. In other words, suspect the diagnosis when a patient presents with multiple neurologic deficits separated by time and space (anatomy).
A number of triggers are known to exacerbate the disease. Infections or trauma may acutely worsen the disease. Pregnancy, especially the 2 to 3 months following birth, may also exacer- bate symptoms. However, there are generally fewer attacks during the pregnancy. Uncompli- cated MS typically has no adverse effects on the outcome of the pregnancy.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
Chapter 11 ● Neurology
Diagnosis. To diagnose MS you have to rely on clinical criteria supplemented with radiologic and laboratory confirmations. The advent of MRI scanning of the brain has dramatically changed the methods by which multiple sclerosis is diagnosed.
MRI of the brain is the most accurate test to diagnose MS, reaching a sensitivity of 85 to 95% in symptomatic persons. Increased T2 and decreased T1 intensity represent the increased water content of demyelinated plaques in the cerebrum and spine. Enhancement of lesions with gadolinium indicates active MS lesions that may enhance for up to 2 to 6 weeks after an exacerbation. MS is an unusual disease in that the best initial test for the diagnosis is also the most sensitive one, namely MRI of the brain and spine.
Evoked response potentials detect slow or abnormal conduction in response to visual, audi- tory, or somatosensory stimuli. The limitation of this test for the diagnosis of MS is that many other neurologic diseases can give an abnormal result. The test is not specific for the diagnosis of MS. As a result, evoked potentials are rarely used to make the diagnosis.
Cerebrospinal fluid (CSF) analysis usually reveals a mild pleocytosis (usually <50 cells/μL) and a total protein that is mildly elevated. A protein level exceeding 100 mg/dL is unusual and should be considered as evidence against the diagnosis of MS. An elevated IgG index (oligoclo- nal bands) is found in 70 to 90% of patients with MS. The finding is nonspecific, and as a result, CSF for oligoclonal banding is recommended only when the MRI is nonconfirmatory but clinical suspicion for MS remains high.
Treatment. The treatment of multiple sclerosis can be divided into disease-modifying therapy, treatment of complications, and treatment for symptomatic relief during an acute exacerba- tion. The specific agents used depend on progression of the disease at the time of diagnosis.
In relapsing-remitting disease, there are 3 disease-modifying agents that have been shown to reduce the number of clinical exacerbations and the number of MRI lesions:
• Interferon-β1a
• Interferon-β1b
• Glatiramer acetate
More importantly, these medications seem to delay the onset of significant disability. Glatiramer is also known as copolymer I.
In secondary progressive disease, interferon-β1b and mitoxantrone have been shown to reduce the number of exacerbations, decrease MRI activity, and delay onset of disability. In patients who receive mitoxantrone, dose-related cardiotoxicity is a concern; mitoxantrone should be given only to patients with a normal ejection fraction. Mitoxantrone is not a first-line agent to prevent disease progression because of its cardiotoxicity. In patients with relapsing-remitting disease or secondary progressive disease who cannot tolerate treatment with IFN-β1b,
IFN-β1a, or glatiramer acetate, you can consider treatment with methotrexate, mitoxantrone, cyclophosphamide, IV immunoglobulin, or azathioprine. ACTH is no longer used.
No approved disease-modifying therapy exists at this time for primary progressive disease.
Mitoxantrone, cyclophosphamide, and natalizumab are not used for a first episode of disease. Natalizumab is associated with progressive multifocal leukoencephalopathy (PML).
The length and intensity of an acute exacerbation are shortened by the administration of glucocorticoids. Typically, an acute exacerbation is treated with 3 days of intense IV steroids followed by a course of oral medication tapered over 4 weeks. In patients with severe disease who are unresponsive to steroid therapy, plasma exchange can be used as an alternative treatment.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
425
USMLE Step 2 l Internal Medicine
For patients with spasticity, baclofen is the most effective medication. Tizanidine and diaz- epam are useful for nocturnal spasticity but are limited in their use for daytime symptoms because they cause intense somnolence. Pain secondary to trigeminal neuralgia and dysesthe- sias responds well to carbamazepine, gabapentin, phenytoin, pregabalin, or tricyclic antide- pressants. Bladder hyperactivity is treated with oxybutynin, whereas urinary retention is treated with bethanechol. Fatigue may be treated with amantadine or fluoxetine. Erectile dysfunction can be treated with sildenafil acetate.
All disease-modifying therapies are relatively contraindicated in pregnancy. Interferon and glatiramer should both be stopped for a pregnancy.
Fingolimod is an oral disease-modifying medication that decreases rates of MRI progression. It prevents lymphocytes from proliferating outside of lymph nodes. Cardiac toxicity can be severe.
Dalfampridine is an oral disease-modifying medication that increases walking speed. It is a unique potassium channel blocker for which the precise mechanism of action (for improved walking speed) is not clearly known.
What is the best initial test in the diagnosis of myasthenia gravis?
Answer: D
A 67-year-old woman is brought to the clinic complaining of forgetfulness. She states that recently she has been forgetting common phone numbers and the name of her mailman, whom she has known for 25 years. Her past medical history is significant for hypertension, coronary artery disease, and high cholesterol. Her physical examination is unremarkable.
Cognitive function is measured by various mental functions, including memory, concentra- tion, language, praxis, visuospatial functioning, and executive functions. “Dementia” refers to loss of memory with impairment of any other cognitive function sufficient to interfere with social or occupational functioning.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
426
Chapter 11 ● Neurology
There are more than 100 identifiable causes of dementia in the elderly.
• Reversible causes include hypothyroidism, vitamin B12 deficiency, hepatic or uremic encephalopathy, CNS vasculitis, syphilis, brain abscess, brain tumor (primary or metastatic), medications (especially anticholinergics), obstructive sleep apnea, central sleep apnea, trauma, subdural hematoma, normal pressure hydrocephalus (NPH), and depression.
• Irreversible causes include progressive multifocal leukoencephalopathy, Alzheimer disease (60–80% of all cases), dementia with Lewy bodies, frontotemporal degenera- tion including Pick disease, vascular dementia including multi-infarct dementia and Binswanger disease, and Creutzfeldt-Jakob disease (CJD).
Clinical Presentation. The most common cause of dementia is Alzheimer disease. Typically, patients will present with problems in memory and visuospatial abilities that generally occur early in the course of the disease. Social graces can be retained despite significant loss of cognitive decline. Hallucinations and personality changes typically occur late in the course of the disease.
Mild cognitive impairment refers to memory loss without dysfunction of other cognitive domains. These patients have a higher risk of developing Alzheimer disease later in life but do not have Alzheimer disease. The rate of progression is 15–20% per year.
Alzheimer disease is, by definition, the loss of memory as well as other cognitive disturbances, such as aphasia, agnosia (the failure to identify entities despite intact sensory function), apraxia, or the loss of the ability to make plans and execute them. There is no single diagnostic test for Alzheimer disease.
Patients with frontotemporal dementias such as Pick disease will typically present with personality changes early in the course of their disease, with relative sparing of their visuospa- tial function. Social, interpersonal, and emotional abnormalities precede memory impairment. Frontotemporal dementia is often noted primarily by the family because the patient lacks insight into their condition. There is no proven therapy for this condition.
Dementia with Lewy bodies (DLB) can be confused with delirium and is characterized by fluctuating cognitive impairment.
Dementia secondary to Parkinson disease should be accompanied by clinical findings consis- tent with that disease. Recurrent visual hallucinations are also characteristic.
Dementia secondary to CJD is characterized by a shorter (weeks to months), more aggressive course than Alzheimer disease. Patients with CJD will present with dementia and myoclonus. Variant CJD is bovine spongiform encephalopathy (BSE). BSE is from the ingestion of prions from affected cattle. The diagnosis of CJD is by rapidly progressive dementia, myoclonus, ataxia, and the presence of 14-3-3 protein in the CSF. EEG may also help diagnose. These criteria can eliminate the need for brain biopsy.
Vascular dementia is divided into multi-infarct dementia, which typically has a stepwise progression associated with discrete cerebrovascular events, and Binswanger disease, involving the subcortical white matter, which presents with a slowly progressive course.
Normal pressure hydrocephalus will present with prominent gait abnormalities early in the course of the disease that usually precede the onset of cognitive impairment. There will also be associated urinary incontinence.
Diagnosis. All patients with cognitive impairment should be assessed with a Mini Mental Status Examination (MMSE) to identify the areas of cognitive impairment.
Note
The prevalence of dementia is 1–5% at ages 65–69, and rising to 45% by age 100. Only 5% of Alzheimer disease is inherited.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
427
USMLE Step 2 l Internal Medicine
Initially, the workup should focus on ruling out reversible causes of the dementia. If a reversible cause is identified, it should be treated, with the hope that cognitive function can be recovered. Laboratory studies should include a complete blood count (CBC), electrolytes, calcium, creatinine, liver function studies, glucose, thyroid-stimulating hormone (TSH), vitamin B12, RPR, and HIV.
Brain imaging is most useful for patients who have a focal neurologic exam, seizures, gait abnormalities, and an acute or subacute onset of their symptoms. EEG and CSF evaluation are not necessary except for NPH-opening pressure. No CSF marker is proven beneficial with the exception of 14-3-3 protein in CJD.
Treatment. Treatment of dementia revolves around insuring that the family and the patient have the proper medical and emotional support to cope with the disease. Caregivers are at an increased risk for depression and anxiety. Their concerns and frustrations should be addressed at frequent intervals.
Raising the level of acetylcholine in CSF benefits patients with Alzheimer disease. Pharmaco- therapy with donepezil has been shown to improve cognitive function in mild to moderate dementia. Other anticholinesterase inhibitors (rivastigmine, galantamine) appear to have similar efficacy.
Memantine is a disease-modifying drug used in advanced disease either alone or with a cholinesterase inhibitor. Memantine seems to be neuroprotective and reduces the rate of progression of disease.
Huntington disease is a genetic degenerative brain disorder caused by the presence of the HD gene located on chromosome 4p. The gene contains a CAG trinucleotide repeat expansion that codes for a protein called huntingtin. The HD mutation leads to abnormal cleavage of the huntingtin protein, interfering with nuclear mechanisms, and causing cell death.
The disease is inherited in an autosomal dominant fashion. Successive generations tend to have the disease occurring at an earlier age. This is called anticipation.
Clinical hallmarks of the disease include chorea and behavioral disturbance. Onset is usually in decade 4 or 5 of life, and can begin with either chorea or behavioral change.
The personality changes consist of irritability, anger, paranoia, or signs of depression. Antisocial behavior may develop.
The chorea changes may begin as fidgeting that progresses to sudden movements of the trunk or limbs. Gait is poorly coordinated and has a choreic quality. Memory is usually preserved until late in the disease but lack of judgment, disinhibition, and inattention are early manifestations. There is frequently an associated depression. Dementia becomes severe later in the disease.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
428
Chapter 11 ● Neurology
Diagnosis is made by genetically testing for the presence of the CAG trinucleotide DNA repeat expansion. There is a 50% chance of passing it on to children. CT scanning shows cerebral atrophy. Atrophy of the caudate nucleus is severe later.
Tetrabenazine helps the movement disorder of Huntington disease but will not reverse or cure the underlying disease process. Death occurs 15–20 years after the diagnosis. Haloperidol or clozapine can be used to control behavioral changes.
PARKINSON DISEASE
Parkinson disease is a neurologic syndrome resulting from the deficiency of the neurotrans- mitter dopamine as a consequence of degenerative, vascular, or inflammatory changes in the basal ganglia. There are numerous causes.
• Drugs, including neuroleptic agents (haloperidol, chlorpromazine), antiemetics (metoclopramide), alpha-methyldopa, and reserpine
• Poisoning from MPTP, carbon monoxide, cyanide, and manganese
• Any structural lesion around the basal ganglia (trauma, tumor, abscess, infarct)
• Survivors of encephalitis can develop postencephalitic Parkinsonism.
Clinical Presentation. The cardinal manifestations of Parkinson disease are bradykinesia (manifested by slow movements, mask facies, reduction of automatic movements), cogwheel rigidity, postural instability, and resting tremor. A useful mnemonic is to think of Mr. Parkin- son as a fine BRITish gentleman.
Bradykinesia Rigidity (cogwheel) Instability (postural) Tremor (resting)
There are a number of “Parkinson plus” syndromes, which are characterized by their relative lack of response to therapy with levodopa/carbidopa.
Parkinsonism + vertical gaze palsy = supranuclear palsy Parkinsonism + prominent ataxia = olivopontocerebellar atrophy
Parkinsonism + prominent orthostatic hypotension = Shy-Drager syndrome (now called
multiple-system atrophy)
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
429
USMLE Step 2 l Internal Medicine
Several other diseases can imitate Parkinsonism. Severe depression can cause a paucity of sponta- neous movement that can mimic Parkinsonism. Essential tremor can be mistaken for the tremor of Parkinson disease, but the lack of other neurologic symptoms and a positive family history of tremor and its amelioration with alcohol distinguish the two entities. A normal pressure hydro- cephalus can present with ataxia and gait disturbances, which can also be mistaken for Parkinson disease. The presence of dementia and urinary incontinence with dilated ventricles on a CT scan of the head can help identify this disorder. Huntington disease can present with akinesia and chorea. The positive family history and dementia usually suggest the correct diagnosis.
Diagnosis. The diagnosis of Parkinson disease is a clinical one. It is important to identify any secondary causes of a patient’s Parkinsonism that are potentially reversible. There is no diagnostic test of choice that can identify patients with Parkinson disease.
Treatment. There are many medications available for the treatment of Parkinson disease. The underlying pathophysiology that causes Parkinson disease is the imbalance of dopaminergic (too little) and cholinergic (too much) tone on the basal ganglia. Thus, medical treatment revolves around increasing dopaminergic tone or decreasing cholinergic tone on the basal ganglia.
Not surprisingly, the medications available for the medical treatment of Parkinson disease directly stimulate dopamine receptors (carbidopa/levodopa, dopamine agonists), indirectly increase the amount of dopamine available (COMT inhibitors, selegiline, amantadine), or block acetylcholine stimulation of the basal ganglia (benztropine, trihexyphenidyl).
Direct-acting dopamine agonists such as pramipexole or ropinirole can be used alone as initial therapy or in combination with small doses of levodopa/carbidopa. Two other dopamine agonists are bromocriptine and cabergoline. All of them are less efficacious than levodopa.
Dopamine agonists do, however, have less dyskinetic side effects. Bromocriptine and pergolide are ergot derivatives and can cause cardiac toxicity.
The first step when considering what medication to start with is evaluating the patient’s functional status. Patients with an intact functional status are managed differently from patients with a compromised functional status.
Patients with intact functional status (less bradykinesia) are not generally given carbidopa/levodopa as initial therapy. Such patients are started on anticholinergic medication when they are age <60.
This is particularly true for those in whom tremor is the predominant symptom. When age >60, the treatment of choice is amantadine. The reason why anticholinergics are relatively contraindicated in elderly patients is because the side effects (dry mouth, urinary retention, constipation, confusion/ hallucinations) occur more frequently and severely. Anticholinergics such as benztropine and trihexyphenidyl are used mostly to relieve tremor and rigidity. Avoid with BPH and glaucoma.
For patients with compromised functional status (more significant bradykinesia), the best initial therapy is carbidopa/levodopa. Carbidopa inhibits extracerebral dopa-decarboxylase, allowing more of the levodopa to reach the central nervous system, where it is needed.
Levodopa is the precursor to dopamine. Carbidopa protects the levodopa from breakdown in the periphery, ensuring its secure delivery to the central nervous system. There are several late complications to carbidopa/levodopa therapy: Dyskinesia (abnormal movements), akathisia (restlessness), and “on-off” phenomena are all disconcerting to the patient. All of these late side effects are termed “response fluctuations” and can be managed by using a sustained release form of carbidopa/levodopa, adding a dopamine agonist, selegiline, or a COMT inhibitor, or restricting the main protein meal to the night. COMT inhibitors are tolcapone and entaca- pone. They are always used in conjunction with levodopa to help reduce the dose or modify response fluctuations. COMT inhibitors have no effect alone; they decrease the metabolism of the levodopa. They are an adjunct to the use of levodopa to reduce adverse effects.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
430
Chapter 11 ● Neurology
Selegiline was once thought to slow the progression of the disease. Selegiline can be used in those with a declining or fluctuating response to levodopa. Selegiline offers mild symptomatic benefit in early disease. Rasagiline is a newer version.
Surgery should only be considered for patients who cannot tolerate or respond adequately to medical therapy. The procedures usually performed are pallidotomy or thalamotomy. The placement of deep brain stimulators is also effective when placed in the globus pallidus or subthalamic nuclei. Surgical therapy is a last resort.
BENIGN ESSENTIAL TREMOR
This is an idiopathic disorder consisting of an isolated tremor of the hands, head, or both. The lower extremities tend to be spared. Essential tremor can be worsened by the use of caffeine or beta agonists. Examination reveals no other abnormalities. Although the level of disability tends to be limited, there can be interference with manual skills such as the ability to write. It is characteristic of this disorder that there is an improvement with the use of alcohol. The patient will describe shaky hands, which improve with 2–3 drinks.
There is no specific diagnostic test for this disorder. Treatment is propranolol. If propranolol is ineffective, alternate medications are primidone, alprazolam, and clozapine. If no medical therapy is effective, thalamotomy is indicated.
RESTLESS LEG SYNDROME
Restless leg syndrome (RLS) is an idiopathic condition resulting in a sensation of creeping and crawling dysesthesia within the legs, leading to involuntary movements during sleep. Often the condition is brought to attention because of multiple bruises sustained by the sleep partner.
The condition can be familial and is exacerbated by sleep deprivation, caffeine, and pregnancy. There is also an association with uremia, iron deficiency, and peripheral neuropathy.
There is no specific diagnostic test for this disorder. Treatment is a dopamine agonist such as pramipexole or ropinirole, although some patients may need levodopa/carbidopa. Other thera- pies are narcotics and benzodiazepines.
Clinical Recall
Which of the following is a characteristic feature of Creutzfeldt-Jakob disease?
Memory loss without dysfunction of other cognitive domains
Gradual loss of memory with other cognitive disturbances
Memory impairment with social, interpersonal, and emotional problems
Stepwise progression of cognitive decline
Rapidly progressive dementia with myoclonic jerks
Answer: E
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
431
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
CDhearmptaetroTloitglye
1#2
Learning Objectives
❑ Describe the mechanism of bullous and blistering diseases and approaches to treatment
❑ List the common dermatologic parasitic diseases, treatments, and common side effects
❑ Outline the treatment of skin and ulcer infections, including decubitis (pressure) ulcers and acne
❑ Describe the presentation and management of scalp, hair, and scaling disorders (eczema), and papulosquamous dermatitis
❑ Provide an overview of toxin-mediated diseases, hypersensitivity, and toxin-mediated diseases
❑ Describe benign lesions, precancerous lesions, and malignant diseases of the skin and their treatment and prognosis
Meissner corpuscle
Epidermis
Dermis
Stratum corneum Stratum lucidum
Stratum granulosum Stratum spinosum Stratum basale Sweat gland duct Arrector pilus
Sebaceous gland Sweat gland Root sheath
Bulb Papilla
Figure 12-1. Skin
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc.
and the National Board of Medical Examiners.
433
USMLE Step 2 l Internal Medicine
Note
Pemphigus vulgaris is a much more serious and potentially life-threatening disease than pemphigoid.
BULLOUS/BLISTERING DISEASES
Pemphigus Vulgaris
Pemphigus vulgaris is an autoimmune disease of unclear etiology in which the body essen- tially becomes allergic to its own skin. Antibodies are produced against antigens in the intercellular spaces of the epidermal cells. They attack the “glue” that holds the epidermal cells together. “Pemphix” is from the Greek word for bubble, which is what a bulla looks like before it is broken. Pemphigus vulgaris is most often idiopathic, but ACE inhibitors or penicillamine can occasionally cause it.
Vulgaris occurs in patients age 30s and 40s. It occurs prominently in the mouth and starts there. The oral lesions are erosions, not bullae. The bullae are very thin and flaccid and break easily. This leads to the loss of large volumes of skin surface area, so it acts like a burn. This is because the bullae occur from destruction within the epidermis, making them thinner and more fragile. The presence of the Nikolsky sign (the easy removal of skin by just a little pressure from the examiner’s finger, pulling the skin off like a sheet) is seen in pemphigus vulgaris, staphylococcal scalded skin syndrome, and toxic epidermal necrolysis.
The lesions of pemphigus vulgaris are painful, not pruritic.
The most accurate diagnostic test is to biopsy the skin and to use immunofluorescent stains. These stains will detect intercellular deposits of IgG and C3 in the epidermis.
Treatment is with systemic glucocorticoids, such as prednisone. Topical steroids will not
be sufficiently strong. Before the invention of steroids, pemphigus vulgaris was often fatal, with patients dying of sepsis and dehydration—just like a burn patient. For those in whom steroids are ineffective or not tolerated, you can use azathioprine, mycophenolate, or cyclophosphamide. Rituximab and IVIG are also effective.
Pemphigoid is 2× as common as pemphigus vulgaris and occurs in elderly persons age 70s and 80s. It can also be drug induced with sulfa drugs, including furosemide, penicillamine, and others.
The defect occurs at the dermo-epidermal junction, so the layer of skin that separates off is much thicker. Because the fracture of the skin causing the blisters is deeper, the bullae are thicker walled and much less likely to rupture. Oral lesions are rare. Because the bullae are tense and intact, the skin is better protected. There is no dressing for skin as good as skin itself. Hence, there is much less fluid loss, and infection is much less likely as compared with pemphigus vulgaris. Mortality is much less likely in bullous pemphigoid.
The most accurate diagnostic test is a biopsy with immunofluorescent antibodies at the dermo-epidermal junction (basement membrane).
Systemic steroids, such as prednisone, are the standard means of treatment. Tetracycline or erythromycin combined with nicotinamide is the alternative to steroids. Use topical steroids only if no oral lesions are present.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
434
Chapter 12 ● Dermatology
Porphyria Cutanea Tarda
Pathogenesis. Porphyria cutanea tarda is a disorder of porphyrin metabolism. Deficiency of the enzyme uroporphyrinogen decarboxylase results in an abnormally high accumulation of porphyrins, which then leads to a photosensitivity reaction. The test question should give a history of HIV, alcoholism, liver disease, chronic hepatitis C, or a woman taking oral contra- ceptives. The liver disease may be from any cause but is most likely to involve chronic infec- tious hepatitis or hemochromatosis because porphyria cutanea tarda is associated with increased liver iron stores. Diabetes is found in 25% of patients.
Clinical Presentation. Fragile, nonhealing blisters are seen on the sun-exposed parts of the body, such as the backs of the hands and the face. This leads to hyperpigmentation of the skin in general and hypertrichosis of the face.
Diagnosis. The diagnostic test is a level of urinary uroporphyrins. Uroporphyrins are elevated 2–5× above the coproporphyrins in this disease.
Treatment. The best initial step in management is to stop drinking alcohol (although it is unlikely to be effective) and to discontinue all estrogen use. Combine treatment with barrier sun protection, such as clothing, because most sunscreens do not seem to block the wave- length of light causing the dermal reaction. The most effective therapy to use if this is insuffi- cient is phlebotomy to remove iron. Deferoxamine is used to remove iron if phlebotomy is not possible. Also, the antimalarial drug chloroquine increases the excretion of porphyrins.
DRUG ERUPTIONS/HYPERSENSITIVITY
Urticaria
Acute urticaria is a hypersensitivity reaction most often mediated by IgE and mast cell activation, resulting in evanescent wheals and hives. It is a type of localized, cutaneous anaphylaxis, but without the hypotension and hemodynamic instability. The most common causes of acute urticaria are allergic reactions to medications, insect bites, and foods, and occasionally, the result of emotions. The most common medications are aspirin, NSAIDs, morphine, codeine, penicillins, phenytoin, and quinolones. ACE inhibitors are also associated with urticaria, as well as angioedema. The most common foods are peanuts, shellfish, toma- toes, and strawberries. Contact with latex in any form can also cause urticaria.
Clinical Presentation. Acute urticaria lasts <6 weeks in duration and two-thirds of cases are self-limited. Chronic urticaria lasts >6 weeks in duration and is associated with pressure on the skin, cold, or vibration. Pressure on the skin resulting in localized urticaria is also known as dermatographism. In acute cases, the onset of the wheals and hives is usually within 30 minutes and lasts for <24 hours. Itching is prominent. In patients with chronic urticaria lasting
>6 weeks, you should investigate the etiology.
Treatment. Urticaria is treated with H1 antihistamines. Severe, acute urticaria is treated with older medications, such as diphenhydramine (Benadryl™), hydroxyzine (Atarax™), or cypro- heptadine. If it is life-threatening, use H2 antihistamines when H1 antihistamines fail and add systemic steroids. Chronic therapy is with newer, nonsedating antihistamines, such loratadine, desloratadine, fexofenadine, or cetirizine. Astemizole and terfenadine should never be used and are no longer marketed; they cause potentially fatal rhythm disturbances particularly
when combined with other medications, such as macrolide antibiotics, because of their effect on the hepatic P450 system.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
435
USMLE Step 2 l Internal Medicine
Note
For urticaria:
Answer “terfenadine” or “astemizole” only when the test question asks what will kill the patient or which is the most dangerous medication.
Answer “desensitization” when the trigger cannot be avoided, e.g., a beesting in a farmer. Beta-blocker medications must be stopped prior to desensitization because they inhibit epinephrine, which may be used if there is an anaphylactic reaction.
A morbilliform rash is a milder version of a hypersensitivity reaction compared with urticaria. This is the “typical” type of drug reaction and is lymphocyte mediated.
The rash resembles measles and is usually secondary to medications that the patient is allergic to, such as penicillin, sulfa drugs, allopurinol, or phenytoin. It is a generalized, maculopapular eruption that blanches with pressure. The reaction can appear a few days after the exposure and may begin even after the medication has been stopped.
Antihistamines are effective, and steroids are rarely necessary.
Although erythema multiforme (EM) may be caused by the same types of medications that cause urticaria and morbilliform rashes (penicillins, phenytoin, NSAIDs, and sulfa drugs), the most common cause of EM is a reaction to infection. The majority of cases follow infection with herpes simplex or Mycoplasma.
The most characteristic feature of EM is target-like lesions that occur especially on the palms and soles. These lesions can also be described as “iris-like.” Bullae are not uniformly found.
EM of this type usually does not involve mucous membranes.
Treatment is antihistamines and treatment of the underlying infection.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
436
Chapter 12 ● Dermatology
Figure 12-3. Erythema Multiforme
Stevens-Johnson syndrome (SJS) is sometimes called erythema multiforme major. It can be difficult to distinguish from toxic epidermal necrolysis (TEN) and, in fact, the two diseases may be considered a spectrum of severity of the same disorder. All of these disorders may arise as a hypersensitivity response to the same set of medications, such as penicillins, sulfa drugs, NSAIDs, phenytoin, and phenobarbital.
Clinical Presentation. SJS usually involves <10 to 15% of the total body surface area, and the overall mortality rate is <5 to 10%. There is mucous-membrane involvement in 90% of cases, most often of the oral cavity and the conjunctivae, although there may be extensive involve- ment of the respiratory tract.
Treat patients with early admission to a burn unit, withdrawal of the offending drug, and supportive care. Respiratory-tract involvement may be so severe as to require mechanical ventilation. Death occurs from a combination of infection, dehydration, and malnutrition.
There is no proven benefit for steroids. The best initial therapy for severe disease is IV immuno- globulins. Other therapies of unclear value are cyclophosphamide, cyclosporine, and thalidomide.
Toxic Epidermal Necrolysis
Toxic epidermal necrolysis (TEN) is the most serious version of a cutaneous hypersensitivity reaction. Mortality may be 40−50%.
Much more of the body surface area (BSA) is involved and may range from 30−100%. The Nikolsky sign is present, and the skin easily sloughs off. TEN has certain features similar to staphylococcal scalded skin syndrome; however, TEN is drug induced as opposed to being caused by a toxin coming from an organism.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
437
USMLE Step 2 l Internal Medicine
Clinical Pearl
Always do a chest x-ray on a patient with EN, to exclude sarcoidosis.
A biopsy of EN lesions will show nonspecific inflammation.
Diagnosis of TEN is usually clinical. The most accurate diagnostic test is a skin biopsy, which will reveal full thickness epidermal necrosis. Skin biopsy is usually not necessary.
Treatment. Sepsis is the most common cause of death, but prophylactic systemic antibiotics are not indicated. Systemic steroids are not effective and may, in fact, decrease survival.
Fixed Drug Reaction
Fixed drug reaction is a localized allergic drug reaction that recurs at precisely the same anatomic site on the skin with repeated drug exposure. It is not known why the reactions are anatomically localized and do not become generalized morbilliform rashes. The most com- monly implicated drugs include aspirin, NSAIDs, tetracycline, and barbiturates.
Fixed drug reactions are generally round, sharply demarcated lesions that leave a hyperpig- mented spot at the site after they resolve.
Discontinue the offending drug, and treat the reactions with topical steroids.
Erythema nodosum (EN) is a localized inflammatory condition of the skin or panniculitis. It is secondary to recent infections or inflammatory conditions. It is also associated with preg- nancy. The most common causes of EN are recent streptococcal infections, coccidioidomyco- ses, histoplasmosis, sarcoidosis, inflammatory bowel disease, syphilis, TB, and hepatitis.
Enteric infections such as Yersinia also cause the disorder.
EN consists of multiple painful, red, raised nodules on the anterior surface of the lower extremities. They are extremely tender to palpation. They do not ulcerate, and they generally last about 6 weeks.
Diagnosis. ASLO titers can help determine who has recently had a streptococcal infection if there is no other etiology apparent from the history.
Treat the underlying disease and use analgesics and NSAIDs. Potassium iodide solution can be used when patients do not respond to symptomatic therapy. EN is usually a self-limiting condi- tion.
Clinical Recall
A 23-year-old woman from Bangladesh presents with seizure disorders. Prior to initiating treatment, which of the following should you check to avoid Stevens-Johnson syndrome?
HLA-B27
HLA-B57
HLA-B1502
HLA-B5801
Answer: C
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
438
Chapter 12 ● Dermatology
INFECTIONS
Fungal Infections
Tinea pedis, cruris, corporis, versicolor, capitis, and onychomycosis
All of the superficial fungal infections of the body share a number of common characteristics leading to the same answer on the test for similar questions for each of these diseases. “Superfi- cial fungal infections” refer to those infections limited to the skin, nails, and hair. Remember, though, that these answers would not be valid for more deep-seated, life-threatening infec- tions, such as fungal endocarditis, meningitis, or abscesses.
Clinical Presentation and Diagnosis. All superficial fungal infections of the skin, hair, and nails are primarily diagnosed by their visual appearance and confirmed by a potassium hydrox- ide (KOH) test of the skin. The leading edge of the lesion on the skin or nails is scraped with a scalpel to remove some of the epithelial cells or some of the nail and hair. KOH has the ability to dissolve the epithelial cells and collagen of the nail, but does not have the ability to melt away the fungus. Hence, a KOH preparation gives an immediate diagnostic answer by reveal- ing fungal hyphae. This is particularly characteristic in tinea versicolor, where the Malassezia furfur (Pityrosporum orbiculare) organism appears in a “spaghetti and meatballs” pattern.
The most accurate test is to culture the fungus. This is usually not clinically practical because molds that grow on the skin (dermatophytes) take up to 6 weeks to grow even on specialized fungal media. A specific species usually does not need to be isolated in most cases, unless it is an infection of the hair or nails. In the case of nail and hair infections, oral therapy is neces- sary, and it is important to be precise because there are fewer medications that can be used to effectively treat onychomycosis. Tinea tonsurans is the cause of >90% of cases of tinea capitis.
Treatment. For onychomycosis (nail infection) or hair infection (tinea capitis), the medica- tions with the greatest efficacy are oral terbinafine or itraconazole. These medications are used for at least 6 weeks for fingernails and 12 weeks for toenails. Terbinafine is potentially hepato- toxic, and it is important to periodically check liver function tests. Griseofulvin must be used for 6 to 12 months in the treatment of fingernails and has much less antifungal efficacy than terbinafine. Griseofulvin is no longer recommended in the treatment of onychomycosis of the toenails. In the treatment of tinea capitis, griseofulvin is recommended for 6 to 8 weeks.
The other fungal infections of the skin that don’t involve hair or nails may be treated with any of the following topical medications: ketoconazole, clotrimazole, econazole, terbinafine, micon- azole, sertaconazole, sulconazole, tolnaftate, or naftifine. There is no clear difference in efficacy or adverse effects between them when used topically. Ketoconazole has more adverse effects when used systemically, such as hepatotoxicity and gynecomastia. This is why ketoconazole is not a good choice for onychomycosis. There is no topical form of fluconazole. Fluconazole is also less efficacious for dermatophytes of the nails when used systemically.
Antifungal medications generally should not be used in combination with topical steroids, unless a diagnosis has been confirmed. Steroids in a cream can relieve redness and itching and give the appearance of improvement even in impetigo and contact dermatitis.
Tinea versicolor
Tinea versicolor is a skin infection characterized by multiple macules (usually asymptomatic), varying in color from white to brown. It is caused by Pityrosporum orbiculare (Malassezia furfur).
Note
Drug of choice for oral antifungal treatment:
Tinea capitis and onchomycosis
– Terbinafine or itraconazole
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
439
USMLE Step 2 l Internal Medicine
Clinical Presentation. Tan, brown, or white scaling macular lesions that tend to coalesce; found on chest, neck, abdomen, or face. Lesions do not tan.
Diagnosis. Skin scrapings examined with 10% KOH under a microscope. The classic descrip- tion is of “spaghetti and meatballs,” which refers to the hyphae and spores that can be seen in the KOH prep.
Treat with topical selenium sulfide, clotrimazole, ketoconazole, or oral itraconazole. Consider local or systemic therapy based on the amount of surface area involved.
Clinical Correlate
Tinea versicolor has some additional features that are important in its management. It presents with lesions of different colors from tan to pink (hence the name versicolor). The lesions often do not tan, and they present with pale areas in the middle of a normal tan. This can be distinguished from vitiligo by the fact that vitiligo has no pigmentation, whereas tinea versicolor presents with altered pigmentation. The organism may also be contagious. A KOH preparation and fungal culture are used in the same manner as for the other dermatophytes. The main therapeutic difference is the use of topical selenium sulfide every 2 to 3 weeks versus oral therapy with itraconazole or fluconazole. This is not because of antifungal resistance; it is because tinea versicolor is much more likely to involve large amounts of body surface area so it is difficult to cover this volume of skin with an ordinary topical cream or lotion.
Candidiasis is a yeast infection usually involving skin and mucous membranes, but it can also be systemic. It is caused by Candida albicans. It usually spreads in patients with decreased host defenses, i.e., those with increased susceptibility due to systemic antibacterial therapy, obesity, DM, corticosteroid or antimetabolite therapy, pregnancy, debilitating disease and blood dyscrasias, or HIV.
Intertriginous infection: Well-demarcated, erythematous, itchy, exudative patches, usually rimmed with small red-based pustules that occur in the groin, gluteal folds (diaper rash), axilla, umbilicus, and inframammary areas.
Vulvovaginitis: White or yellowish discharge with inflammation of the vaginal wall and vulva. Common in pregnant women and patients with diabetes mellitus.
Oral candidiasis (thrush): White patches of exudates on tongue or buccal mucosa
Candidal paronychia: Painful red swelling around the nail
Diagnosis. Potassium hydroxide on slide to visualize fungal forms. Culture is definitive.
Treatment
Topical nystatin, clotrimazole, miconazole, ciclopirox, econazole, or terconazole
Systemic amphotericin in serious invasive infections. Fluconazole in less serious infections. Candida paronychia requires systemic therapy.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
440
Chapter 12 ● Dermatology
Bacterial Infections
Antistaphylococcal antibiotics
The most common bacterial organisms to cause skin infections of any kind are Staphylococcus and Streptococcus. Antibiotics used to treat Staphylococcus are dicloxacillin, cephalexin (Keflex™), or cefadroxil (Duricef™). Cefadroxil, cefazolin, or cephalexin are the preferred agents. If a patient is allergic to penicillin, but the reaction is only a rash, then cephalosporins can be safely used.
There is far less than 5% cross-reaction between penicillins and cephalosporins. The IV equiva- lents of oral dicloxacillin include oxacillin and nafcillin. The IV equivalent of cefadroxil is cefazolin.
If the penicillin reaction is anaphylaxis then cephalosporins cannot be used. The alternative antibiotics that will treat the skin are macrolides, such as erythromycin, azithromycin, clar- ithromycin, or the newer fluoroquinolones (levofloxacin or moxifloxacin). Ciprofloxacin will not adequately cover the skin. Vancomycin is only for IV use for skin infections, and oral vancomycin is not absorbed. Oral therapy for MRSA is with clindamycin, TMP/SMX, or doxycycline. The ultimate form of oral MRSA therapy is linezolid.
Impetigo
Impetigo is a superficial, pustular skin infection, seen mainly in children (ecthyma is an ulcer- ative form of impetigo), with oozing, crusting, and draining of the lesions. It is a superficial bacterial infection of the skin largely limited to the epidermis and not spreading below the dermal-epidermal junction. It is caused by group A beta-hemolytic Streptococcus and S. aure- us (bullous impetigo).
• Because it is limited to the epidermis, the purulent material is easily able to express itself through the surface; therefore, the patient history will describe the infection with words such as “weeping,” “oozing,” “honey colored,” or “draining.”
• Occurs more often in warm, humid conditions, particularly when there is poverty and crowding of children. This is because it is both contagious and autoinoculable.
• More common on arms, legs, and face
• Begins as maculopapules and rapidly progresses to vesicular pustular lesions or bullae. The crusts are described as having a golden or yellow appearance and if untreated can progress to lymphangitis, furunculosis, or cellulitis, and acute glomerulonephritis.
• May cause glomerulonephritis, but it will not cause rheumatic fever
Treatment
• Oral first-generation cephalosporin or semisynthetic penicillin, e.g., oxacillin, cloxa- cillin, dicloxacillin (for severe or widespread cases)
• Topical mupirocin, bacitracin, or retapamulin for mild cases of impetigo
• Penicillin-allergic patients can be treated with macrolides such as clarithromycin or azithromycin.
• TMP/SMZ, clindamycin, or doxycycline for MRSA
Note
Group A streptococci and S. aureus are the most common causes of impetigo.
Note
Retapamulin is a topical antibacterial more active against staph and strep than mupirocin or bacitracin are.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
441
USMLE Step 2 l Internal Medicine
Clinical Pearl Necrotizing fasciitis is commonly associated with
varicella infection, where the
skin lesions are infected by
Streptococcus or Staph.
Erysipelas
Erysipelas is a bacterial infection of a deeper layer of the skin than impetigo. Erysipelas involves both the dermis and epidermis and is most commonly caused by group A Streptococcus (pyogenes).
Because it involves lymphatic channels in the dermis, erysipelas is more likely to result in fever, chills, and bacteremia.
Often involves the face, giving a bright red, angry, swollen appearance
Usually bilateral, shiny red, indurated edematous tender lesions on the face, arms, and legs
Lesions are often sharply demarcated from the surrounding normal skin
Differentiate from herpes, contact dermatitis, and angioneurotic edema
Treatment. Semisynthetic penicillin or first-generation cephalosporin if you cannot distin- guish it from cellulitis; penicillin (if Streptococcus is certain).
Cellulitis is a bacterial infection of the dermis and subcutaneous tissues with Staphylococcus and Streptococcus. Cellulitis is characterized by redness, swelling, and warmth and tenderness of the skin. Because it is below the dermal-epidermal junction, there is no oozing, crusting, weeping, or draining.
Treatment. Cellulitis is treated with the antibiotics prescribed for erysipelas on the basis of the severity of the disease. If there is fever, hypotension, or signs of sepsis or if oral therapy has not been effective, then the patient should receive IV therapy. Oxacillin, nafcillin, or cefazolin is the best therapy. Treatment is generally empiric because injecting and aspirating sterile saline for a specific microbiologic diagnosis has only a 20% sensitivity. Oral therapy for MRSA is with clindamycin, TMP/SMX, or doxycycline.
Folliculitis, furuncles, and carbuncles
Folliculitis, furuncles, and carbuncles represent 3 degrees of severity of staphylococcal infec- tions occurring around a hair follicle. Occasionally, folliculitis can be the result of those who contract Pseudomonas in a whirlpool or from a hot tub.
As folliculitis worsens from a simple superficial infection around a hair follicle, it becomes a small collection of infected material known as a furuncle. When several furuncles become confluent into a single lesion, the lesion becomes known as a carbuncle, which is essentially a localized skin abscess. Folliculitis is rarely tender, but furuncles and carbuncles are often extremely tender.
Treatment. Folliculitis mainly can be treated with warm compresses locally without the need for antibiotics. If antibiotics are required, mupirocin is the best choice. Furuncles and carbun- cles require treatment with systemic antistaphylococcal antibiotics, and in the case of carbun- cles, should be administered intravenously. Treatment with dicloxacillin, cephalexin, or cefadroxil is acceptable. A large furuncle or carbuncle will also require surgical drainage.
Necrotizing fasciitis
Necrotizing fasciitis is an extremely severe, life-threatening infection of the skin. It starts as a cellulitis that dissects into the fascial planes of the skin. Streptococcus and Clostridium are the most common organisms because they are able to produce a toxin that further worsens the damage to the fascia. Diabetes increases the risk of developing fasciitis.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
442
Chapter 12 ● Dermatology
The features which distinguish necrotizing fasciitis from simple cellulitis are a very high fever, a portal of entry into the skin, pain out of proportion to the superficial appearance, the presence of bullae, and palpable crepitus.
Laboratory evidence of necrotizing fasciitis is an elevated creatine phosphokinase and an x-ray, CT, or MRI that show air in the tissue or necrosis. All of these lab methods of establishing a diagnosis lack both sensitivity and specificity. Surgical debridement is the best way to confirm the diagnosis and is also the mainstay of therapy.
Treatment. Surgery is the mainstay of therapy. The best empiric antibiotics are the beta-lac- tam/beta-lactamase combination medications, such as ampicillin/sulbactam (Unasyn™), ticarcillin/clavulanate (Timentin™), or piperacillin/tazobactam (Zosyn™). If there is a definite diagnosis of group A Streptococcus (pyogenes), then treat with clindamycin and penicillin.
Without adequate therapy, necrotizing fasciitis has an 80% mortality rate.
Paronychia
Paronychia is an infection loculated under the skin surrounding a nail. It is generally treated with a small incision to allow drainage and with antistaphylococcal antibiotics. The antistaphy- lococcal antibiotics are dicloxacillin, cefadroxil, or cephalexin orally, or oxacillin, nafcillin, or cefazolin intravenously.
Viral Infections
Herpes simplex
Herpes simplex infections of the genitals are characterized by multiple, painful vesicles. The vesicles are usually obvious by examination, and antibiotic therapy should be initiated imme- diately without waiting for results of the tests.
Diagnosis is done with active lesions only. In the event that the diagnosis is not clear or the lesions have become confluent into an ulcer, the best initial test is a Tzanck smear.
• The Tzanck smear is somewhat nonspecific in that it will determine only that the infection is in the herpesvirus family.
• The Tzanck smear detects multinucleated giant cells and is similar in technique to a Pap smear. A scraping of the lesion is immediately placed on a slide and sprayed with fixative.
• Tzanck smears have 75% sensitivity in diagnosing facial herpetic lesions, but only 40% sensitivity in diagnosing genital lesions.
The most accurate diagnostic test is a viral culture, which will grow in 24−48 hours. Serology is not useful for diagnosing herpes infections.
Immediate therapy is with oral acyclovir, famciclovir, or valacyclovir. Topical acyclovir has extremely little efficacy; it will slightly improve resolution in primary lesions and will do absolutely nothing for recurrent herpes simplex lesions. Topical penciclovir has some use for oral herpetic lesions, but it must be applied every 2 hours. The treatment of acyclovir-resistant herpes is with foscarnet.
Note
If an exam question presents an obvious clinical case with crepitus, pain, high fever, and a portal of entry, you should answer “surgery” (not a test, such as an x-ray) as the best initial step.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
443
USMLE Step 2 l Internal Medicine
Centers for Disease Control and Prevention
Figure 12-4. Herpes Simplex Lip
Chickenpox is primarily a disease of children. Complications of varicella are pneumonia, hepa- titis, and dissemination. Episodes of dermatomal herpes zoster, also known as shingles, occur more frequently in the elderly and in those with defects of the lymphocytic portion of the immune system (i.e., leukemia, lymphoma, HIV, or those on steroids).
The vesicles are 2−3 mm in size at all stages of development and are on an erythematous base.
Diagnosis. Although the Tzanck prep and viral culture are the best initial and most accurate diagnostic tests, they are generally not necessary because little else will produce a band of vesicles in a dermatomal distribution besides herpes zoster.
Treatment. Chickenpox is generally not treated with antivirals. If the child is immunocompro- mised or the primary infection occurs in an adult, then acyclovir, valacyclovir, or famciclovir should be given.
Steroid use is still not clearly beneficial, although the best evidence for efficacy is in elderly patients with severe pain. The rapid administration of acyclovir still has the best efficacy for decreasing the risk of postherpetic neuralgia.
Other treatments for managing the pain are gabapentin, tricyclic antidepressants, and topical capsaicin. The most effective analgesic specific for postherpetic neuralgia is gabapentin.
Nonimmune adults exposed to chickenpox should receive varicella zoster immunoglobulin within 96 hours of the exposure in order for it to be effective.
Molluscum contagiosum
Molluscum contagiosum is skin-colored, waxy, umbilicated papules. It is caused by poxvirus. It is commonly seen in children; frequency is increased in patients infected with HIV.
Small papules appear anywhere on the skin (genital and pubic area), usually by venereal contact, and are asymptomatic. The lesions have a central umbilication. They can be transmit- ted by skin-to-skin contact or sexually.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
444
Chapter 12 ● Dermatology
Diagnosis is made mainly on appearance. Lab testing is rarely, if ever, necessary. Giemsa stain will show large cells with inclusion bodies.
Treat with freezing, curettage, electrocautery, or cantharidin.
Clinical Recall
What is the most appropriate management for onychomycosis of the toenails?
PO griseofulvin
PO terbinafine
Topical itraconazole
PARASITIC INFECTIONS
Scabies
Scabies is a parasitic skin infection characterized by superficial burrows, intense pruritus, and secondary infections. It involves vesicular eruptions resulting from the females of the Sarcoptes scabiei (hominis) burrowing into the skin. It is caused by the itch mite, Sarcoptes scabiei.
Transmission is by skin-to-skin contact.
Scabies primarily involves the web spaces of the hands and feet. It also produces pruritic lesions around the penis, breasts, and axillary folds. Itching can be extreme. Because Sarcoptes scabiei is quite small, all that can be seen with the naked eye are the burrows and excoriations around small pruritic vesicles. Scabies often spares the head. Immunocompromised patients, such as those with HIV, are particularly vulnerable to an extremely exuberant form of scabies with severe crusting and malodorousness, known as Norwegian scabies.
Diagnosis in all cases is confirmed by scraping out the organism after mineral oil is applied to a burrow; however, skin scrapings are usually not necessary and are not routinely done.
Treat with permethrin. Lindane (Kwell) has equal efficacy, but also greater toxicity. Lindane should not be used in pregnant women. Ivermectin is a suitable alternative and is given as oral therapy if the disease is extensive. Treat Norwegian scabies with a combination of permethrin and ivermectin.
Pediculosis
Pediculosis is skin infestation by lice. It is caused by the following:
• Head: Pediculus humanus capitis
• Body: Pediculus humanus corporis
• Pubic area: Phthirus pubis (“crab louse”)
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
445
USMLE Step 2 l Internal Medicine
Note
Differential Diagnosis
SSSS:
From an infection
Splits off only the superficial granular layer of skin
TEN:
From drug toxicity
Full-thickness split of skin
Patients present with itching, excoriations, erythematous macules and papules, and sometimes secondary bacterial infection. Diagnosis is made by direct examination of the pubic area, axillae, scalp, and other hair-bearing surfaces for the organism (louse or nits). Treat with permethrin or lindane (Kwell).
TOXIN-MEDIATED DISEASES
Toxic Shock Syndrome
Toxic shock syndrome (TSS) is a systemic reaction to a toxin produced from Staphylococcus attached to a foreign body. The majority of cases now are not from a menstrual source, such as a tampon or vaginal packing. Nasal packing, retained sutures, or any other form of surgical material retained in the body can promote the growth of the type of staphylococci that produces the toxin.
Because there is no single specific test, cases are matters of definition. TSS is defined as the presence of 3 or more of the following findings:
Involvement of the mucous membranes of the eyes, mouth, or genitals
Raises creatinine, creatine phosphokinase, and liver function tests
Often produces hypocalcemia (usually because of a diffuse capillary leak syndrome that drops the albumin level)
Streptococcal toxic shock syndrome is essentially the same.
To treat, remove the source of the infection and give vigorous fluid resuscitation, pressors (e.g., dopamine), and antibiotics. Empiric treatment is with clindamycin plus vancomycin until cultures return. In confirmed cases of methicillin-sensitive strains, treat with clindamycin plus an antistaphylococcal medication (oxacillin, nafcillin). In methicillin-resistant strains (MRSA), use vancomycin or linezolid.
Staphylococcal Scalded Skin Syndrome
Staphylococcal scalded skin syndrome (SSSS) is transmitted through physical contact with surroundings. It most commonly occurs in infants, young children, and the immunocompromised.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
446
Chapter 12 ● Dermatology
SSSS is mediated by a toxin from Staphylococcus. The major presentation is the loss of the superficial layers of the epidermis in sheets. Nikolsky sign is present. It is markedly different from toxic shock syndrome in that there is normal BP and no involvement of the liver, kidney, bone marrow, or CNS.
Patients should be managed in a burn unit and given oxacillin or other antistaphylococcal antibiotics. Consider vancomycin because of possible MRSA.
BENIGN AND PRECANCEROUS LESIONS
The predominant method of distinguishing between benign and malignant lesions is by the shape and color of the lesion. Benign lesions, such as the junctional or intradermal nevus, do not grow in size and have smooth, regular borders with a diameter usually <1 cm. In addition, they are homogenous in color, and this remains constant. Biopsy is the most accurate method of making a diagnosis, and benign lesions need to be removed only for cosmetic purposes.
visualsonline.cancer.gov
Figure 12-5. Dysplastic Nevus
Seborrheic Keratosis
Seborrheic keratosis is a benign condition with hyperpigmented lesions occurring in the elderly. It has no malignant potential and no relation to either actinic keratosis or seborrheic dermatitis. Lesions have a “stuck on” appearance, and are most common on the face, shoul- ders, chest, and back.
Lesions are removed only for cosmetic purposes with liquid nitrogen or curettage.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
447
USMLE Step 2 l Internal Medicine
Figure 12-6. Seborrheic Keratosis
Actinic keratosis presents with precancerous lesions occurring on sun-exposed areas of the body in older persons. Lesions occur more often in those with light skin color. They contain chromosomal abnormalities, and although only 1:1,000 lesions progresses to squamous cell cancer, an individual patient may have dozens of them. Hence, the rate of transformation to squamous cell cancer is 0.25% per patient.
Although the lesions are usually asymptomatic, they can be tender to the touch and lighter in color.
Lesions should be removed with cryotherapy, topical 5 fluorouracil (5-FU), imiquimod, topical retinoic-acid derivatives, or even curettage. Advise patients to use sunscreen to prevent progression and recurrence.
MALIGNANT DISEASES
Melanoma
Superficial spreading melanoma is the most common type of malignancy, accounting for 70% of cases. The rate of occurrence of melanoma is rising faster than any other cancer in the United States.
Malignant lesions grow in size, have irregular borders, are uneven in shape, and have inconsis- tent coloring. Lentigo maligna melanoma arises on sun-exposed body parts in the elderly.
Acral-lentiginous melanoma arises on the palms, soles of feet, and nail beds.
Biopsy diagnosis is best performed with a full-thickness sample because tumor thickness is by far the most important prognostic factor.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
448
Chapter 12 ● Dermatology
Table 12-1. Ten-Year Survival Rates for Melanoma
Lesion Size (mm) | Survival Rate |
<0.76 | 96% |
0.76–1.69 | 81% |
1.7–3.6 | 57% |
>3.6 | 31% |
Melanoma is removed by excision. Huge 5-cm margins are not routinely indicated. The size of the margin is determined by tumor thickness.
• Melanoma in situ needs only 0.5-cm margin
• Lesions <1 mm in thickness get 1.0-cm margin
• Lesions 1- to 2-mm in depth get 2-cm margin
• Lesions >2 mm in depth get 2- to 3-cm margin
There is no definitive chemotherapy for any form of skin cancer. Interferon seems to reduce recurrence rates.
National Cancer Institute
Figure 12-7. Melanoma
Squamous Cell Carcinoma
Squamous cell carcinoma makes up 10–25% percent of all skin cancers. It develops on
sun-exposed skin surfaces in elderly patients. It is particularly common on the lip, where the carcinogenic potential of tobacco is multiplicative.
Ulceration of the lesion is common. Metastases are rare (3–7%).
Diagnosis is confirmed with biopsy. Treatment is surgical removal. Radiotherapy can be used for lesions that cannot be treated surgically.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
449
USMLE Step 2 l Internal Medicine
Basal Cell Carcinoma
Basal cell carcinoma makes up 65−80% of all skin cancers. It has a shiny or “pearly” appear- ance. Metastases are very rare (<0.1%).
Diagnosis is confirmed with shave or punch biopsy. Treatment is surgical removal. Mohs microsurgery has the greatest cure rate: instant frozen sections are done to determine when enough tissue has been removed to give a clean margin.
FU can be used in the treatment of superficial lesions.
Figure 12-8. Basal Cell Carcinoma
The causative organism of Kaposi sarcoma is Human herpes virus 8. These are purplish lesions found on the skin, predominantly of patients with HIV and CD4 <100/mm3.
Treatment is antiretroviral therapy to raise CD4 count. When that does not occur, the specific chemotherapy for Kaposi sarcoma is liposomal doxorubicin hydrochloride or vinblastine.
Clinical Recall
What is the margin of excision of a suspected melanoma that has an in-depth thickness of 1.5 mm?
0.5 cm margin
2 cm margin
3 cm margin
4 cm margin
Answer: B
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
450
Chapter 12 ● Dermatology
SCALING DISORDERS (ECZEMA)/PAPULOSQUAMOUS DERMATITIS
Psoriasis
The etiology of psoriasis is unknown. Silvery scales develop on the extensor surfaces, either locally or extensively. Nail pitting is a common accompaniment. The Koebner phenomenon is the development of lesions with epidermal injury.
Treatment. Salicylic acid is used to remove heaped-up collections of scaly material so that the other therapies can make contact. If the disease is relatively localized, topical steroids are used. Severe disease also needs coal tar or anthralin derivatives. To avoid the long-term use of steroids, which can cause skin atrophy, and to avoid coal tars, which are messy to use, substi- tute topical vitamin D and vitamin A derivatives. The vitamin D derivative most frequently used is calcipotriene. Tazarotene is a topical vitamin A derivative.
All patients should use emollients such as Eucerin™, Lubriderm™, or mineral oil. When >30% of the body surface area is involved, it is difficult to routinely use topical therapy to control disease. Ultraviolet light in that case is the most rapid way to control extensive disease. The most severe, widespread, and progressive forms of the disease can be controlled with metho- trexate; however, it has the highest toxicity and may cause liver fibrosis.
The newest therapy is immunomodulatory biologic agents, such as alefacept, efalizumab, etanercept, and infliximab. These are monoclonal antibodies that target defects in the immune system, such as tumor necrosis factor.
Wikipedia, James Heilman, MD
Figure 12-9. Psoriasis
Atopic Dermatitis
Atopic dermatitis is an extraordinarily pruritic disorder characterized by high IgE levels. Red, itchy plaques appear on the flexor surfaces. In children, lesions are common on the cheeks and scalp. Adults present with lichenification.
Active disease is managed with topical steroids, antihistamines, coal tars, and phototherapy.
• Use antistaphylococcal antibiotics if there is impetiginization of the skin
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
451
USMLE Step 2 l Internal Medicine
Use topical immunosuppressants such as tacrolimus and pimecrolimus to decrease dependence on steroid use
Every effort must be made to avoid scratching; the topical tricyclic doxepin can be used to help stop pruritus
Preventive therapy is achieved by keeping the skin moist with emollients, avoiding hot water and drying soaps, and using only cotton clothes, as patients with this condition are extremely sensitive to drying.
Seborrheic Dermatitis
An oversecretion of sebaceous material and a hypersensitivity reaction to a superficial fungal organism, Pityrosporum ovale, underlie seborrheic dermatitis. Patients present with “dandruff,” which may also occur on the face. Scaly, greasy, flaky skin is found on a red base on the scalp, eyebrows, and in the nasolabial fold.
Treatment is low-potency topical steroids such as hydrocortisone, or topical antifungals in the form of shampoo such as ketoconazole or sulfide. Zinc pyrithione is also used as a shampoo.
Stasis dermatitis is a hyperpigmentation built up from hemosiderin in the tissue. It occurs over a long period, from venous incompetence of the lower extremities leading to the microscopic extravasation of blood in the dermis. There is no way to reverse this problem. Prevention of progression is with elevation of the legs and lower-extremity support hose.
Contact dermatitis is a hypersensitivity reaction to soaps, detergents, latex, sunscreens, or neomycin over the area of contact. Jewelry is a frequent cause, as is contact with the metal nickel from belt buckles and wristwatches. It can occur as linear, streaked vesicles, particularly when it is from poison ivy.
A definitive diagnosis can be determined with patch testing. Once the causative agent has been identified, treat with antihistamines and topical steroids.
phil.cdc.gov
Figure 12-10. Contact Dermatitis Due to Poison Ivy
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
452
Chapter 12 ● Dermatology
Pityriasis Rosea
Pityriasis rosea is a pruritic eruption that often begins with a “herald patch.” It is mild, self- limited, and usually resolves in 8 weeks without scarring.
It is erythematous, salmon colored, and looks like secondary syphilis, except that it spares the palms and soles and has a herald patch. The lesions on the back appear in a pattern like a Christmas tree.
This is a clinical diagnosis. VDRL/RPR is negative. Treat very itchy lesions with topical steroids.
DECUBITUS (PRESSURE) ULCERS
Decubitus ulcers are chronic sores that occur in the pressure areas of the body, where bone is closer to the skin. They are often associated with patients who are immobilized or bedridden.
Clinical presentation is in stages.
• Stage I lesions consist of nonblanchable redness.
• Stage II lesions result in destruction of the superficial epidermis or partial destruc- tion of the dermis.
• Stage III lesions have destroyed the full thickness of the skin but not the fascia.
• Stage IV lesions show destruction all the way to the bone.
Diagnosis. Never culture a swab of the superficial ulcer or drainage from the ulcer. It will be impossible to determine whether it is a genuine infection or simply colonization. A definitive microbiologic diagnosis is often obtained only in the operating room after debridement.
The major theme of treatment is to relieve pressure. If the lesions are definitely infected, then antibiotics are useful.
HAIR
Alopecia Areata
Alopecia areata is an autoimmune disease in which antibodies attack the hair follicles and destroy hair production. Most cases will resolve spontaneously over time. Immediate treat- ment is localized steroid injection into the area of hair loss.
Telogen Effluvium
Telogen effluvium is the loss of hair in response to an overwhelming physiologic stress, such as cancer or malnutrition. Treatment is correction of the underlying stress or disease.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
453
USMLE Step 2 l Internal Medicine
ACNE
The contributing organism for acne is Propionibacterium acnes. Pustules and cysts occur, which rupture and release free fatty acids, which in turn causes further irritation. Acne is more common in girls, but boys have more severe disease.
Patients present both with closed comedones (which are white) and open comedones (which are black). The discharge, although purulent, is odorless.
Treat mild disease with a topical antibiotic (clindamycin, erythromycin, sulfacetamide) plus the possible addition of the bacteriostatic agent benzoyl peroxide. If the attempts to control the load of bacteria locally are ineffective, use topical retinoids.
Treat moderate disease with benzoyl peroxide plus a retinoid (tazarotene, tretinoin, adapalene).
Treat severe cystic acne with an oral antibiotic (minocycline, tetracycline, clindamycin, oral isotretinoin). Oral retinoic-acid derivatives are a strong teratogen.
Which of the following treatment strategies is used to control extensive
Answer: D
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
454
RadioloCghyap/ItmeraTgiitnlge
1#3
Learning Objectives
List the indications and common abnormal findings for chest x-ray, abdominal x-ray, PET scan, bone scan
Answer questions about different approaches to visualizing the CNS
This concise section should help you understand the types of tests offered in radiology.
CHEST X-RAY
The most basic radiologic examination is a chest x-ray. Standard x-rays are based on the degree of density of tissue and how much x-ray energy each type of tissue will absorb.
The closer a bone structure is in density, the greater the energy it will absorb.
Therefore, because bones block the most amount of x-ray energy, they will come out white on the film.
Conversely, air absorbs or blocks the least amount of energy and thus will appear darkest.
Chest x-rays are not routine screening tests. There is no routine screening of the general popula- tion for cancer or tuberculosis. You can do a chest x-ray if the PPD skin test is positive, but that is not the same thing as just doing a general screening.
Most x-rays are posterior-anterior (PA) films. The x-ray plate is placed in front of the chest, and the patient leans forward against the plate. The x-ray beam is directed from posterior to anterior. The patient must be able to stand for a PA film to be performed.
Anterior-posterior (AP) films are less accurate but must be done if the patient is too ill or unstable to stand up.
All patients with central venous lines or chest tubes
Unstable patients, such as those in intensive care
The single greatest difference between the film types is heart size:
AP films will show a heart size that is artificially enlarged; that is because the heart is more anterior in the chest and will therefore cast a wider shadow.
AP films will show a heart >50% of the total transthoracic diameter, while normal PA films will show a heart <50%.
Note
The phenomenon produced by AP film is no different than holding your hand in a light shined against a wall. The farther your hand is away from the wall, the larger your hand’s shadow will appear.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
455
USMLE Step 2 l Internal Medicine
Note
The right hemidiaphragm will appear higher on a lateral
ray and a PA film because the liver pushes it upward.
Technical Aspects of Normal Film Quality
When examining a chest x-ray, first assess the film for its technical quality. If the patient’s body is abnormally rotated, the film will be less accurate. You can determine this by seeing if the trachea and the spinous apophysis are midway between the clavicles.
Perform chest x-ray when the patient is holding in a full inhalation. There should be at least 10 ribs visible, counting from top to bottom.
An underexposed film will have the structures appearing too white, while an overex- posed film will have the blood vessels appearing too dark (preventing one from accurately assessing the blood vessels).
Note that on a PA film, the right hemidiaphragm is typically higher than the left. That is because the liver is underneath the right hemidiaphragm, pushing it up.
Expiratory films are used when one is looking for a pneumothorax. The lungs will appear smaller because less air will remain in the lungs on expiration. Because a pneumothorax is air outside the lungs in the pleural space, this air will appear relatively larger. The volume of air in the pleural space does not decrease on exhalation.
Lateral chest x-ray will determine whether a structure in the chest is more anterior or poste- rior. For example, it can determine whether a mass that is visible in the center of the mediasti- num on a PA film is posterior, making it more likely to be a neurally derived tumor attached to the spinal cord or an anterior mass. Anterior mediastinal masses are from the thymus, thyroid, lymph nodes, or a teratoma.
Lateral x-ray also has a greater sensitivity for the detection of small pleural effusions.
On a PA film, at least 100-200 mL of fluid needs to be present to even begin to see an effusion. Each hemithorax can contain 3 liters of fluid if it is filled to capacity.
These figures represent the amount of fluid needed to barely begin seeing “blunting,” or obliteration, of the costophrenic angle.
On a lateral x-ray, the right hemidiaphragm is the one crossing the heart shadow.
Decubitus Film
Decubitus film helps detect the presence of a pleural effusion. It is taken with the patient lying on his side, and is employed when blunting or obscuration of the costophrenic angle is seen on a PA or lateral x-ray.
Effusions will move and form a layer on the side of the chest wall. Infiltrates from alveolar disease do not move with gravity. You cannot determine if an effusion is infected just from its appearance on an x-ray.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
456
Chapter 13 ● Radiology/Imaging
COMMON DISORDERS SEEN ON CHEST X-RAY
COPD/Emphysema
The most common appearance of COPD on a chest x-ray is related to hyperinflation of the lung.
Leads to a darkening of the lung fields because more air is present
Trapped air flattens the diaphragm and gives the impression of an elongated or tubular-shaped heart because it has been stretched down
Leads to increased anterior/posterior diameter, or “barrel chest”
Bullae may be seen (large, air-filled cavities that can give thin, white lines on a chest x-ray as walls of the cavities press up against each other)
Pneumonia
Lobar pneumonia causes a whitening of each individual lobe of the lung because of greater density of the lung
“Silhouette” sign is present (border between the affected lobe and surrounding denser structure is obscured)
Density of the lung increases because of alveolar infiltration to the point where it takes on the density of the nearby heart or diaphragm; thus, one can no longer tell where the lung ends and the nearby denser structure begins
Lower lobe pneumonia gives a silhouette over each half of the diaphragm. Right middle-lobe pneumonia obscures the right heart border and will not pass the minor or horizontal fissure seen on a PA chest x-ray. Upper-lobe infiltration will not pass the major fissure, and this is more easily seen on a lateral x-ray. You cannot determine a specific microbiologic etiology from the x-ray alone.
Diseases of the lung outside the airspace but in the interstitial membrane give a fine, lacy appearance visible in most, if not all, of the lobes. Disorders which give intersti- tial infiltrates include Pneumocystis pneumonia, Mycoplasma, viruses, chlamydia, and sometimes Legionella. Noninfectious etiologies of an interstitial infiltrate are pulmo- nary fibrosis secondary to silicosis, asbestosis, mercury poisoning, berylliosis, byssino- sis (from cotton), or simply idiopathic pulmonary fibrosis. As the long-standing disorders become worse and more chronic, a greater degree of fibrosis occurs and leads to greater thickening of the membrane (described as reticular-nodular and, later, honeycombing).
Note
Interstitial Syndromes of the Lung include:
Sarcoidosis Histiocytosis X
IPF (interstitial pulmonary
fibrosis) Tumor Failure Asbestosis
Collagen disorders Environmental Dust
Drugs
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
457
USMLE Step 2 l Internal Medicine
Note
The subtle radiologic finding with Kerley B line is less important today in the evaluation of congestive heart failure, since the advent of echocardiography.
The majority of pulmonary vascular flow is normally at the base of the lungs because of gravity. When there is fluid overload, the blood vessels toward the apices become fuller (called pulmonary vascular congestion or “cephalization” of flow). The term cephalization is used because more flow is moving toward the head.
The other findings associated with CHF are cardiomegaly, effusions, and Kerley B lines.
Kerley B lines are the least important. They are small, horizontal lines at the bases that repre- sent fluid in the interlobular septa. Each lung has several lobes. When fluid builds up outside the lobes, this is known as a pleural effusion. When fluid builds up within each lobe, in between the lobules, this is known as a Kerley B line.
Chest x-rays are routinely used to determine the appropriate position of central venous lines and both endotracheal and chest tubes. The proper position of the tip of an endotracheal tube is 1 to 2 cm above the carina. It is important to keep some space above the carina so that when the head moves forward, the tube does not push into the carina, which is extremely uncomfortable and will provoke coughing. The tip of central venous lines is at the junction of the superior vena cava and the right atrium, at the point where the right mainstem bronchus is seen. The tip of the line should not be fully inside the atrium because this can irritate the heart and may provoke an arrhythmia.
Air under the Diaphragm
When there is perforation of an abdominal hollow organ, such as the duodenum, air is released and is visible under the diaphragm. The proper film to detect this is a chest x-ray taken in the upright position. This will allow the air to collect under the diaphragm, which should be easily visible. Abdominal x-rays do not always visualize the top of the diaphragm because of differences in body size. Chest x-rays always visualize the top of the diaphragm.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
458
Chapter 13 ● Radiology/Imaging
Imaging Tools for Lung Parenchyma
High resolution CT scan provides greater detail than a chest x-ray or CT scan because of
1 mm cut. This has a sensitivity of 95% and a specificity of close to 100% for lung parenchy- mal disease. High resolution CT scan is indicated in the following conditions:
Detecting metastatic lesions, solitary nodules, bullae, bronchiectasis, and diffuse parenchymal disease (i.e., idiopathic lung diseases)
To determine the type of lung biopsy required and site of biopsy
Clinical Recall
Which of the following is an indication for getting an expiratory chest x-ray?
Pleural effusion
Tuberculosis
COPD
Pneumothorax
Congestive heart failure
Answer: D
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
459
USMLE Step 2 l Internal Medicine
ABDOMINAL X-RAY
Compared with chest x-rays, standard abdominal films without barium contrast provide far less information.
Beneficial only in the detection of an abdominal obstruction, such as an ileus or a volvulus
Do not reliably detect mass lesions, polyps, cancer, ascites, IBD
Use the following guidelines for detection:
Mass lesions in all abdominal organs are best detected with CT scan or MRI of the abdomen.
Polyps are best detected by colonoscopy.
Ascites are visualized by U/S or CT scan.
IBD, diverticulosis, and cancer are best detected by endoscopy or barium study of the bowel.
Although 80−90% of kidney stones (nephrolithiasis) can be seen on abdominal films, they are also best detected by U/S or CT scan. Only 10−15% of gallstones can be detected on an abdominal film because most of them do not calcify.
Pancreatic calcifications can be detected in 30−50% of patients with chronic pancreatitis.
Sonography is used for evaluation of abdominal and pelvic pathology. Sonograms should be employed first for evaluation of the biliary tract because of their accuracy in evaluating dilation and obstruction of the ducts. The majority of cholelithiasis should be detected with sonography because cholesterol gallstones should be easily visible by sonography. The majority of nephroli- thiasis is visible by sonography, although there is less accuracy in detecting stones in the ureters because they become retroperitoneal structures.
Sonography is useful in the evaluation of masses in the liver, spleen, pancreas, and pelvis, as well as for evaluating the presence of ascites. Despite this accuracy, CT scanning tends to have a greater sensitivity and specificity for the abdomen and pelvis. Sonography is particularly valuable in the evaluation of pregnant patients because it avoids radiation exposure to the fetus. Although less accurate, sonography is also practical in patients who have an absolute contraindication to the use of IV contrast. A total of 1:10,000 patients have a life-threatening reaction to the use of iodinated contrast agents.
There is very little utility of sonography in the evaluation of thoracic structures because the ribs block the sound waves. Also, sonography in the evaluation of intracranial structures, such as the brain, is not recommended because the skull blocks the sound waves.
Endoscopic U/S involves introducing a sonographic device into the abdomen at the end of an endoscope. Endoscopic U/S is extremely accurate in evaluating pancreatic pathology that is not easily visualized on CT scanning, such as a gastrinoma. Pancreatic lesions can also be effectively evaluated in this way.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
460
Chapter 13 ● Radiology/Imaging
Endoscopic Retrograde Cholangiopancreatography
Endoscopic retrograde cholangiopancreatography (ERCP) is an endoscopically introduced contrast procedure designed to visualize the biliary tract and pancreatic structures. ERCP is for therapy. The endoscope is introduced into the small bowel, and a catheter is placed through the sphincter of Oddi. Contrast is injected through the catheter. This allows extremely accurate visualization of the pancreatic ductal and biliary systems. ERCP is excellent for detecting stric- tures, stones, and neoplastic causes of obstruction. The other advantages of ERCP are the ability to perform therapy with the removal of these stones, to dilate strictures, and to perform biopsies. The scope does not routinely go up the sphincter of Oddi because it is too large to pass. MRCP is an MRI alternative to ERCP. It is less invasive than ERCP but does not allow an intervention.
The most common complication of ERCP is acute pancreatitis (around 10% in some series). Most of the time the pancreatitis is mild.
Barium Studies
Barium studies of the large bowel are never as accurate for colonic pathology as is endoscopy. In addition, you cannot biopsy with barium studies or perform therapeutic procedures, such as cautery or epinephrine injection for bleeding. The upper GI series is never as accurate as is upper endoscopy for the same reasons.
However, barium studies of the esophagus are a good test to start with for the evaluation of esophageal pathology. Barium esophagoram is particularly good for the detection of strictures, rings, and webs, or Zenker diverticulum. Barium is not as accurate as an upper endoscopy for the detection of esophageal cancer because a biopsy is required. (Endoscopy is far superior for the detection and therapy of esophageal varices as well.) Barium is not as accurate as manom- etry for the confirmation of the diagnoses of achalasia or muscular disorders, such as diffuse esophageal spasm and nutcracker esophagus.
Capsule Endoscopy
The ileum and jejunum are the hardest parts of the bowel to visualize by radiologic studies or endoscopy. In the past, a “push enteroscopy” was performed by introducing an extremely long, thin scope into the small bowel. Capsule endoscopy is a new technology that allows direct visualization of the small bowel by swallowing a camera that electronically relays thousands of photographic images from the small bowel to a receiver outside the body. The drawback of this procedure is that it is not possible to perform therapeutic interventions in this way. If a patient has GI bleeding that is serious and both upper and lower endoscopy do not reveal the source, then answer “capsule endoscopy” on the exam.
HIDA Scanning
This is a nuclear medicine scan useful only in the detection of acute cholecystitis. HIDA scanning is most useful in patients in whom the diagnosis of cholecystitis is not clear. An abnormal or positive test is the lack of visualization of the gallbladder. This is because the neck of the gallblad- der or cystic duct becomes too edematous to allow the passage of the nuclear material. A normal scan will visualize the gallbladder. An abnormal scan will not visualize or fill the gallbladder.
Note
MRCP: diagnosis ERCP: treatment
Clinical Pearl
Capsule endoscopy is not a screening test to detect colon cancer. Perform capsule endoscopy to evaluate obscure small bowel GI bleeding.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
461
USMLE Step 2 l Internal Medicine
This procedure uses CT scan or MRI to provide a computer-simulated bidimensional or tridimensional image of the air-filled, distended colon.
Clinical Pearl Always check the patient’s glucose before doing a PET
scan. If the glucose is elevated,
the PET scan can be falsely negative.
PET SCANNING
Positron emission tomography (PET) scans are useful in the detection of cancer. They are particularly useful in determining whether lesions that are visible on a CT scan of the chest are malignant or benign. Cancer is typically associated with the increased uptake of fluorodeoxy- glucose. PET scanning is used after chemotherapy to assess for the presence of residual cancer in some patients and can also be used to determine whether a patient is an operative candidate to remove a primary cancer. If the PET scan does not reveal malignancy, then the resection of certain primary cancers, such as lung cancer, is more likely to be successful.
Remember that slow-growing cancers (e.g., bronchoalveolar) may have a negative PET scan. Be careful when evaluating pulmonary nodules with PET scanning.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
462
Chapter 13 ● Radiology/Imaging
CENTRAL NERVOUS SYSTEM VISUALIZATION
In general, the most accurate test for evaluating the central nervous system is magnetic resonance imaging (MRI). The MRI is superior for the detection of stroke, cancer, multiple sclerosis, and infections and in the evaluation of the posterior fossa, such as the cerebellum and brainstem.
The CT scan does not visualize the brainstem well. For example, a stroke is visible on an MRI in >90% of cases within the first 24 hours after its onset, whereas the CT scan needs 3 to 4 days before >90% are visible. This is because the MRI is based on the water content of tissues rather than on the calcium content or simple density of tissue. Within a few hours after the onset of a stroke, the cells begin to swell and increase their water content. This is immediately visible on an MRI, whereas for a CT scan to detect an abnormality, the cells must die to decrease the den- sity of visible cells.
The single exception in which a CT scan is superior to an MRI is in the detection of blood. As soon as bleeding occurs, it is visible on a CT scan. Therefore, the two cases in which a CT scan is a better study are to evaluate head trauma and to exclude hemorrhagic stroke. When a patient arrives within 3 hours of the onset of the symptoms of a stroke, a CT scan is first performed to exclude hemorrhage. This is to see if a patient is eligible for the use of thrombo- lytic therapy within these first 3 hours.
A CT scan is also used first for the detection of subarachnoid hemorrhage. On the first day after the stroke’s onset, the CT scan has 95% sensitivity. The sensitivity diminishes by about 5% per day as the blood is hemolyzed and removed.
Contrast on a scan of the head is indicated primarily for the detection of cancers and infection. When an abscess or neoplastic process is present, there is some disruption of the blood-brain barrier, causing some extravasation of the contrast, which is visible as a contrast, or “ring”- enhancing lesion around the mass.
BONE IMAGING
An x-ray is certainly the first study to implement when evaluating trauma and fracture. Unfortunately, the bone scan has much less specificity and does not reliably distinguish between bone infection and infection of the overlying soft tissue. The MRI is both 90 to 95% sensitive and 90 to 95% specific.
Osteomyelitis
When there is the suspicion of osteomyelitis, then an x-ray is done first. Although plain x-rays lack sensitivity for the first 1 to 2 weeks, the specificity for osteomyelitis is excellent. More than 50% of the calcium content of bone must be lost for osteomyelitis to be visible. The earliest finding of osteomyelitis on an x-ray is elevation of the periosteum. If the film returns normal and there is still suspicion of osteomyelitis, then the best test is an MRI. The MRI and techne- tium nuclear bone scan have the same sensitivity (90–95%); however, the MRI’s specificity is far greater (90–95%). Both studies should become abnormal within 2 days of the onset of osteomyelitis. Therefore, a negative bone scan is very useful if it is normal; it means that there is no osteomyelitis. If it is abnormal, you may still need to perform an MRI.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
463
USMLE Step 2 l Internal Medicine
Clinical Recall
Which of the following findings on CXR will be seen in a patient with a perforated peptic ulcer?
Kerley B lines with vascular cephalization
Blunting of the costophrenic angles with a clear meniscus sign
Pneumoperitoneum
Flattening of the diaphragm with a tubular shaped heart
Interstitial hyperdensities with hilar lymphadenopathy
Answer: C
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
464
OpChhthaapltmeroTloitglye
1#4
Learning Objectives
Describe the presentation and treatment of glaucoma, cataracts, keratitis, uveitis, periorbital cellulitis, retinal diseases, and conjunctival diseases
RETINAL DISEASES
Diabetic Retinopathy
The etiology of diabetic retinopathy is based on damage to the endothelial lining of the small blood vessels of the eye. This is identical in pathogenesis to the damage that diabetes causes to all blood vessels in the body, such as in the heart, kidney, brain, and peripheral nervous system. The endothelial lining of the retinal vessels becomes damaged, leading to progressive occlusion on a microscopic level. The occlusion leads to obstruction and increased pressure.
The earliest form of this adverse effect on the retina is called nonproliferative (or background) retinopathy. It is characterized by dilation of veins, microaneurysms, retinal edema, and retinal hemorrhages. Hemorrhages into the retina are not as damag- ing as intravitreal hemorrhages because they do not obstruct sight.
Proliferative retinopathy is a more advanced form of the disease and is markedly more serious, meaning it progresses more rapidly to blindness. As the microvascular damage to the vessels worsens, these vessels secrete increased amounts of an angiogenesis factor. The vessels are not providing sufficient nutrition to the retina. The vessels themselves exert an increased effort to have more of them produced in an effort to deliver more nutrition and oxygen to the retina. Unfortunately, this “neovascularization,” or new blood vessel formation, leads to the optic nerve getting covered with abnormal new vessel formation. In addition, hemorrhages protrude into the vitreous chamber. Vitreal hemor- rhages are much more serious than microaneurysms or intraretinal hemorrhages because they are much more sight threatening.
The whole point of therapy for diabetic retinopathy is to first prevent the patient from ever progressing to the proliferative phase and, second, to slow down the disease’s progress with laser photocoagulation, if it occurs.
Clinical Presentation. The clinical presentation of diabetic retinopathy is highly variable. There may be very advanced disease occurring with no symptoms. Vision may decrease slowly or rapidly. Vitreal hemorrhages may develop suddenly, and patients will complain of “floaters” in their vision.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
465
USMLE Step 2 l Internal Medicine
Retina-Vitreous Surgeons of Central New York
Figure 14-1. Features of Diabetic Retinopathy
Diagnosis. Screening for the presence of retinopathy should be performed on an annual basis by an ophthalmologist. This is how candidates for fluorescein angiography and laser photoco- agulation are found. Fluorescein helps identify which vessels should undergo laser photoco- agulation. The laser selectively destroys focal areas of the retina and diminishes the production of the angiogenesis factor, which causes the proliferative retinopathy.
Treatment of both stages of diabetic retinopathy involves the attempt to have tight control of glucose, blood pressure, and lipid levels. Proliferative retinopathy additionally involves immediate treatment with laser photocoagulation. Aspirin, clopidogrel, and other platelet- inhibiting medications have shown no benefit. The more tightly the glucose is controlled within the normal range, the slower the progression of the retinopathy. Blood pressure should be controlled to a level of <130/80 mm Hg.
Diabetes is considered by the National Cholesterol Education Program (NCEP) to be the equivalent to coronary artery disease in terms of its effect on cardiac mortality and on LDL targets. Even if there is no evidence of coronary artery disease, the target LDL in a diabetic patient is <100 mg/dL. If the patient is diabetic and has evidence of coronary disease, then the target LDL can be as low as <70 mg/dL. Glucose control is the most effective of these methods of retarding progression of the disease.
Retinal Detachment
A 71-year-old woman presents to the physician with blurry vision in her left eye since that morning. She says it was as if “a curtain came down.” She has had floaters in the periphery of her left eye over the past few weeks but has had no pain or erythema. She has a history of stage I hypertension but is otherwise healthy.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
466
Chapter 14 ● Ophthalmology
Retinal detachment is usually spontaneous, but it may result from trauma. The term rheg- matogenous, which is used to describe the detachment, is from the Greek word for “tear.” The two most common predisposing factors are myopia and surgical extraction of cataracts.
Traction on the retina can also occur from proliferative retinopathy from diabetes, retinal vein occlusion, and age-related macular degeneration.
The most common presentation is blurry vision developing in one eye without pain or redness. The patient may complain of seeing “floaters,” as well as flashes at the periphery of vision.
Sometimes it is described as a “curtain coming down,” as the retina falls off the sclera behind it. Diagnosis is made by ophthalmologic examination.
Treatment. Various methods of trying to reattach the retina are employed. Patients should lean their heads back to promote the chance that the retina will fall back into place. The retina can be mechanically reattached to the sclera surgically, by laser photocoagulation, cryotherapy, or by the injection of expansile gas into the vitreal cavity. The gas will press the retina back into place. A “buckle,” or belt, can be placed around the sclera to push the sclera forward so that it can come into contact with the retina. If all of these methods fail to reattach the retina, then the vitreous can be removed and the retina can be surgically attached to the sclera. The majority (80%) of uncomplicated rhegmatogenous retinal detachments can be cured with one operation, with 15% needing a second operation.
National Eye Institute/National Institutes of Health
Figure 14-2. Retinal Detachment
Age-Related Macular Degeneration
Age-related macular degeneration (ARMD) is the most common cause of legal blindness in older persons in the Western world. The etiology is unknown. ARMD is characterized by the formation of deposits of extracellular material collecting into yellowish deposits seen on ophthalmoscopy. These deposits are known as “drusen.” They are small, granular, subretinal deposits that are age related.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
467
USMLE Step 2 l Internal Medicine
There are 2 types of ARMD:
A dry, or atrophic, form is characterized by slowly progressive visual loss in the elderly. Diagnosis is confirmed by finding clearly visible drusen on dilated eye exam. Dry-type ARMD leads to visual loss of a slow, gradual nature.
A wet, or exudative, form is characterized by the abnormal growth of vessels from the choroidal circulation into the subretinal space. These vessels leak, leading to collec- tions of subretinal fluid and a localized, exudative retinal detachment. Wet type can present with the rapid distortion of vision over weeks to months. Fluorescein angiog- raphy will help confirm the diagnosis of exudative ARMD.
Treatment. There is no clear evidence that any therapy will stop the progression of dry-type ARMD. There is some evidence that zinc, antioxidant vitamins such as vitamins C and E, and beta-carotene may retard progression of the disease.
Wet-type ARMD is treated with VEGF inhibitors ranibizumab and bevacizumab.
Central Retinal Artery Occlusion
There are various etiologies of central retinal artery occlusion: carotid artery embolic disease, temporal arteritis, cardiac thrombi or myxoma, or any of the usual causes of thrombophilia such as factor V Leiden mutation.
Patients present with a sudden, painless, unilateral loss of vision. There is no redness of the eye. Ophthalmoscopy reveals a pale retina, with overall diminished perfusion and a “cherry- red” spot at the fovea. There is also “box-car” segmentation of the blood in the veins.
To diagnose, patients should undergo evaluation with carotid artery imaging, echocardiogra- phy, and evaluation for thrombophilia.
Central retinal artery occlusion is managed in much the same way as for a stroke (cardiovas- cular accident or transient ischemia attack.
Supply oxygen and ocular massage in an attempt to unobstruct the vessel
Also consider acetazolamide and thrombolytics. Anterior chamber paracentesis has been used to try to decompress the pressure in the eye and dislodge the embolus.
Central Retinal Vein Occlusion
Patients with retinal vein occlusion are at particularly high risk for developing glaucoma. They should be monitored for the possible use of laser photocoagulation. Younger patients should be investigated for inherited causes of thrombophilia, such as factor V mutation, protein C deficiency, and antiphospholipid syndromes.
Presentation is similar to retinal artery occlusion: sudden loss of vision without pain, redness, or abnormality in pupillary dilation. Ocular examination by funduscopy reveals disk swelling, venous dilation, tortuosity, and retinal hemorrhages.
Retinal hemorrhage is the main way to distinguish venous obstruction from arterial obstruction. You can’t have a hemorrhage in the retina if you don’t have blood getting into the eye.
There is no specific treatment for retinal vein obstruction.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
468
Chapter 14 ● Ophthalmology
Clinical Recall
Which of the following fundoscopic findings is representative of proliferative diabetic retinopathy?
Dilation of veins, microaneurysms, retinal edema, and retinal hemorrhages
Vitreal hemorrhages with optic nerve concealment by neovascular growth
Floaters, red cells in the vitreous with a wrinkled, detached retina
Yellowish, small, and granular extracellular subretinal deposits
A pale retina with diminished perfusion and a cherry-red spot at the fovea
GLAUCOMA
The precise etiology of glaucoma is not clearly known.
In open-angle glaucoma, the precise etiology of the decrease in the outward flow of aqueous fluid has never been elucidated. Thus, the precise cause of the increase in intraocular pressure is not known.
Acute angle-closure glaucoma can be precipitated by anticholinergic medications such as ipratropium bromide or tricyclic antidepressants; however, most people with narrow angles in their anterior chambers never develop glaucoma.
This disorder accounts for >90% of cases of glaucoma. Patients are asymptomatic for a long time, and this is the reason why it is important to screen older patients.
The first clue to the diagnosis is a cup-to-disk ratio >0.5, which should be confirmed by repeated elevation in intraocular pressure as determined by tonometry.
Treatment is based on decreasing the production of aqueous humor while increasing its drainage.
Medications that decrease the production of aqueous humor are beta-blockers (timolol, betaxolol, levobunolol), alpha-adrenergic agonists (apraclonidine, brimoni- dine), and carbonic anhydrase inhibitors (dorzolamide and brinzolamide).
Medications that increase the outflow of the humor are prostaglandin analogs such as topical latanoprost, travoprost, and bimatoprost. (The prostaglandin analogs can lead to a change in the color of the eyes and a darkening of the eyelid. Pilocarpine is a miotic agent that constricts the pupil to allow greater outflow of the aqueous humor.)
If maximal medical therapy is ineffective in controlling intraocular pressure, consider surgery. Laser trabeculoplasty or surgical trabeculectomy are the most commonly per- formed procedures.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
469
USMLE Step 2 l Internal Medicine
Closed-Angle Glaucoma
Closed-angle glaucoma is often an ophthalmologic emergency precipitated by the use of medications with anticholinergic properties.
It presents with an eye that is red, painful, hard to palpation, and associated with a fixed midpoint pupil. The cornea has a hazy cloudiness, and there is marked diminishment of visual acuity.
Treatment of acute angle-closure glaucoma is an ophthalmologic emergency. Use IV acetazolamide, urea, and osmotic diuretics such as mannitol and glycerol.
Pilocarpine can be used to open the canal of Schlemm, and beta-blockers are used to decrease humor production. If these medical therapies are ineffective, laser trabeculoplasty can be performed.
Cataracts are opacifications of the lens. They are slowly progressive, with a blurring of vision occurring over months to years. Glare from the headlights of cars is particularly a problem when driving at night. Color perception is reduced in general. The etiology of cataracts is unknown, although there is an association with cigarette smoking.
Mature cataracts can be easily seen on physical examination. Earlier-stage disease is seen with a slit lamp.
There is no medical therapy for cataracts. Surgical removal with the placement of an intraocu- lar lens is the standard of care.
Conjunctivitis can occur from any infectious agent, including bacteria, viruses, and fungi.
Bacterial conjunctivitis is often unilateral and presents with a marked purulent discharge from the eye. This is most symptomatic in the morning, when the patient’s eye has developed a significant crust overnight, sometimes making it hard to open the eye. There is less itching compared with viral conjunctivitis. Although the eye can be red, there is a normally reactive pupil, normal ocular pressure, and no impairment of visual acuity.
Viral conjunctivitis is often bilateral, with severe ocular itching and enlarged preau- ricular adenopathy. The eyes are also red, but there is a normally reactive pupil and no photophobia.
Treat bacterial conjunctivitis with a topical antibiotic such as erythromycin ointment, sulfacetamide drops, or topical fluoroquinolones.
Treat viral conjunctivitis symptomatically with topical antihistamine/decongestants. There is no specific microbiologic treatment.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
470
Chapter 14 ● Ophthalmology
Subconjunctival Hemorrhage
Subconjunctival hemorrhage is more dangerous in its appearance than in its actual damage to vision or even the eye itself. The most common cause is trauma, particularly in the presence of thrombocytopenia. The collection of the hematoma stops at the limbus, which is the anatomic connection between the conjunctiva and the cornea. Because this prevents the blood from covering the cornea, there is no impairment of vision.
There is no intraocular or intravitreal damage and hence no impairment of vision. No specific therapy is necessary.
KERATITIS
Keratitis refers to any infection or inflammation of the cornea. Usually, keratitis happens as a result of trauma to the cornea with the inoculation of bacterial or fungal elements into the cornea.
Herpes simplex keratitis is characterized by severe pain in the eye and a sensation that something is caught under the eyelid.
Diagnosis is based on finding a characteristic dendritic pattern over the cornea on fluorescein staining of the eye with examination under a blue light.
Treatment is oral acyclovir, famciclovir, or valacyclovir, plus topical trifluridine 1% solution or idoxuridine.
Note that oral and topical steroids should never be used in an attempt to relieve the inflammation of herpes simplex keratitis. That can markedly worsen the growth of the virus (acting as “fertilizer”).
Cellulitis is caused by Staphylococcus aureus or Streptococcus invading the dermis and subcuta- neous tissues surrounding the eye.
Treatment is an antistaphylococcal penicillin such as oxacillin or nafcillin. In cases of penicillin allergy, use a first-generation cephalosporin such as cefazolin.
UVEITIS
Uveitis occurs when the structures of the uveal tract (the iris, ciliary body, and choroid) become inflamed. It is caused by various systemic inflammatory conditions, such as psoriasis, sarcoidosis, syphilis, Reiter syndrome, and IBD.
Uveitis leads to a painful, red eye with marked photophobia. One clue to diagnosis is pain that occurs even when shining a light in the unaffected eye. This is because of the consensual light reflex in which the affected pupil will constrict even when light is shined in the normal eye.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
471
USMLE Step 2 l Internal Medicine
Diagnosis is made by slit lamp examination. Inflammation of the iris, ciliary body, and choroid is visible. Inflammatory cells may accumulate on the inside of the cornea after they precipitate out of the aqueous humor, rather like an accumulating snowfall. These focal collections are called keratic precipitates.
Basic management, despite the varied underlying conditions, is to treat with topical or systemic steroids.
Clinical Recall
A 32-year-old man presents with redness of his eyes, marked photo- phobia, and normal conjunctiva. Which of the following is the best initial treatment?
Answer: A
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
472
InCdheaxpter Title 00
A
ABCDE discharge recommendations, in ACS, 145
Abdominal aortic aneurysm, screening for, 8
Abdominal imaging ultrasound, 460
x-rays, 460–462
Abdominal pain, lead poisoning and, 384 Abscess
brain, 232–233
lung, 237–238
perinephric, 259–260 Absence (petit mal) seizures, 412 Acanthocytes, 205
Accelerated atherosclerosis, in end-stage renal disease, 299
Acetaminophen, for osteoarthritis, 78 Acetaminophen toxicity, 378–379 Acetylcholine, in dementia
management, 428
Achalasia, 86–87
Achlorhydria, 97
Acid-base disturbances, 305–308
Acid-fast bacilli (AFB), in tuberculosis testing, 244, 245
Acidosis
diabetic ketoacidosis, 43–44 in drowning victims, 401 metabolic, 306–307
renal tubular, 308–310
respiratory, 308
in salicylate toxicity, 386 Acids, toxic exposure to, 381
contraindicated management, 382
Acne, 454
Acquired immune deficiency syndrome (AIDS), 273–278
antiretroviral therapy for, 277–278
breast feeding and, 278 immune system monitoring in,
276–277
Acute bacterial pyelonephritis, 259 Acute bronchitis, 237
Acute coronary syndrome (ACS), 137–149 chest pain quality in, 126 complications of, 146–148
discharge medications after, 145–146 nonatherosclerotic, 148–149
operational classification, 137–138
Acute idiopathic polyneuropathy (Guillain-Barré syndrome), 420–421
Acute kidney injury (AKI), 281–290 Acute leukemia, 209–210
lymphocytic, 209
myelogenous, 209
Acute pancreatitis, 116–118
Acute pericarditis, 272–273
Acute renal failure (ARF), 281–290 Acute respiratory compromise/distress,
evaluating, 330–331
Acute respiratory distress syndrome (ARDS), 357
in drowning victims, 402 hospital admission and, 332
Acute tubular necrosis (ATN), 285–286 Adalimumab (Humira), 67
Adams-Stoke attacks, 178
Addison disease, 54–55
Adefovir, for hepatitis infection, 250 Adenocarcinoma, of lung, 358 Adenomas
pituitary, 13–17
thyroid, 31
Adenomatous polyposis coli (APC) gene, 112
Adenosine, adverse effects of, 189 Adenosine stress test, 135
Adjuvant therapy, in STEMI, 144–145 Adrenal androgen excess, syndromes of, 53 Adrenal crisis, 56
Adrenal glands
cortical regions of, 48–49 diseases of, 48–57
hyperfunctioning, 49–54
hypofunctioning, 54–57
hypopituitarism and, 18 Adrenal hyperplasia
congenital, 52–53
in Cushing syndrome, 49–51 Adrenal insufficiency, 54–56
Adrenal neoplasia, in Cushing syndrome, 49–51
Adrenocorticotropic hormone (ACTH) Addison disease and, 54–55 Cushing syndrome and, 49–51 hypopituitarism and, 18
Adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) therapy, 216
Adult polycystic kidney disease, 311 Adult respiratory distress syndrome.
See Acute respiratory distress syndrome (ARDS)
Advanced cardiac life support (ACLS) algorithm, 187, 362
Afterload increase/reduction,
in HOCM, 170
Age, as IHD risk factor, 132
Age-related macular degeneration (ARMD), 467–468
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
473
USMLE Step 2 CK l Internal Medicine
Air flow/movement, measurement of, 321 Albumin
in hypoparathyroidism, 39 in prerenal azotemia, 283
Alcohol abuse. See also Ethylene glycol poisoning
hypoglycemia and, 48
isopropyl alcohol ingestion, 380 methanol poisoning, 379–380
screening for, 9
Alcohol withdrawal-related syndromes, 390–391
Alcoholic hallucinosis, 390 Alcohols
clearance time, 378
dialysis and, 380
Alkaline phosphatase, primary biliary cirrhosis and, 121
Alkalis, toxic exposure to, 381 contraindicated management, 382
Alkalosis
metabolic, 305–306
respiratory, 306
All-trans-retinoic acid (ATRA), 210 Allergic asthma, 335
Allergic bronchopulmonary aspergillosis (ABPA), 339
Allergic cross-reactivity, with penicillins, 226
Allergic interstitial nephritis (AIN), 286–287 Allergies
anaphylaxis and, 402
asthma and, 335
Allopurinol, gout and, 79, 80
Alopecia areata, 453
Alpha-1 antitrypsin deficiency (AATD) in COPD, 340
liver disease and, 123 Alpha-adrenergic blockers, 318
as antihypertensive, 318
Alpha thalassemia, 198, 199
Alport syndrome, 295
Alveolar-arterial gradient (PAo2–Pao2), 326–327
Alveolar diffusing capacity (DLCO), 322, 324
Alzheimer disease, 427 Aminoglycosides
acute renal failure and, 289 gram-negative bacilli and, 228
as myasthenia gravis therapy, 423
Aminophylline therapy, 336 Amiodarone
abnormal thyroid function caused by, 29
adverse effects, 189
for cardiovascular disease, 188
for ventricular tachycardia, 367, 368 Amnesia, head trauma and, 391 Amoxicillin, for gram-positive cocci, 226 Amphetamines, clearance time, 378 Amphotericin B, acute renal failure and, 289 Ampicillin
for gram-positive cocci, 226 for meningitis, 230
Amyl nitrate, effect on systolic murmurs, 166
Amylase test, in acute pancreatitis, 117 Amyloidosis, 295–296
Amyotrophic lateral sclerosis (ALS), 423–424
Anaerobic bacteria, antibiotics for, 228 Analgesic nephropathy, 290
Anaplastic carcinoma, of thyroid, 32 Anemia, 193–195
in end-stage renal disease, 299 etiology, 193
patient evaluation algorithm, 195 Anesthetics, malignant hyperthermia
stable, 126, 133–136
unstable, 137, 138–140 Angiography
in gastrointestinal bleeding, 115 in IHD, 136
pulmonary, 353–354
in subarachnoid hemorrhage, 396 in unstable angina/NSTEMI, 140
Angioplasty
acute renal failure and, 289
for cerebrovascular accident, 411 Angiotensin-converting enzyme (ACE)
inhibitors, 283–284
in acute coronary syndrome, 146 as antihypertensive, 317
in congestive heart failure, 154–156, 158 Angiotensin receptor blockers (ARBs)
as antihypertensives, 317
for congestive heart failure, 154, 155
Animal bites, 402, 403–404 Anion gap
in renal acidosis, 306–307
in renal tubular acidosis, 309 in salicylate toxicity, 386
Ankylosing spondylitis (AS), 74–75 sacroiliitis in, 75
Anterior cerebral artery (ACA) occlusion, 409
Anterior pituitary, diseases of, 13–19 Anterior-posterior (AP) chest x-rays, 455 Anterior spinal artery occlusion, 407 Anterograde memory loss, head trauma
and, 391
Anti-tissue transglutaminase antibody (IgA), 108, 109
Antiarrhythmics, 189
adverse effects, 189
Antibiotic-associated diarrhea (AAD), 105–106
in acute renal failure, 289 for anaerobic bacteria, 228 in asthma, 336
in COPD, 343
diarrhea caused by, 105–106 in diarrhea management, 104
for gram-negative bacilli, 227–228 for gram-positive cocci, 225–227 in infectious disease, 225–228
in radiation injury management, 401 for skin MRSA, 228
Anticardiolipin antibodies, 65 Anticholinergic drugs
in asthma, 336
in COPD, 341
Anticholinergic poisoning, 388–389 Anticholinesterase inhibitors, in dementia
management, 428 Anticholinesterase therapy, for myasthenia
gravis, 422
Anticipation, Huntington disease and, 428 Anticoagulants. See Warfarin Anticonvulsant therapy, 413
Antidiuretic hormone (ADH) diabetes insipidus and, 19–21
excess of, syndromes associated with, 22
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
474
Index
inappropriate secretion of, syndrome of, 22
pituitary gland and, 11 Antiemetics, in radiation injury
management, 401
Antifungals, 439
Antihistamines, for urticaria, 435 Antihyaluronic acid (AHT) test, 294 Antihypertensive medications, 316–318 Antineutrophil cytoplasmic antibodies
(ANCAs), 64
Wegener granulomatosis and, 82 Antinuclear antibodies (ANAs)
in drug-induced lupus, 70
in rheumatologic disease evaluation, 63–64
in scleroderma, 72
Antiphospholipid antibody syndrome, 65 Antiplatelet therapy
in cerebrovascular accident, 411 in STEMI, 144–145
in unstable angina/NSTEMI, 139 Antipsychotics, in alcohol withdrawal
management, 390, 391
Antiretroviral therapy, 277–278 Antistaphylococcal antibiotics
for bacterial infections of skin, 441 for furuncles and carbuncles, 442
Antistreptolysin (ASO) test, 294 Antithrombin therapy
in STEMI, 145
in unstable angina/NSTEMI, 139 Antivenin, 404
Anxiety, hypertension and, 313 Aortic coarctation, 316
Aortic dissection, 128–129
Aortic regurgitation, 166–167
Aortic stenosis, 164–165
differential diagnosis, 165 effects of maneuvers on, 166
Aortic valve sclerosis, in aortic stenosis differential diagnosis, 165
APACHE score, in acute pancreatitis, 117 Apixaban, 372
Aplastic anemia, 208–209
Argyll Robertson pupil, in syphilis, 253 Arnold Chiari malformation, 406 Arrhythmias. See also Dysrhythmias
digoxin toxicity and, 387 drug therapy for, 189
in hypothermia, 399
supraventricular, 178–183, 367–368 torsade de Pointes, 186–187 ventricular, 184–185
ventricular fibrillation, 365 Arterial blood gases (ABGs)
in acute respiratory compromise/ distress, 331
in adult respiratory distress syndrome, 357
in asthma, 335–336
in carbon monoxide poisoning, 380, 381
in COPD, 342
disturbances in, 326–327
in pulmonary thromboembolism, 352 Arteritis, temporal, 83, 417
evaluating patient with, 61–62 psoriatic, 74, 76
septic, 81, 261–262 Arthrocentesis, septic arthritis and, 81 Arthropathies
in acute pancreatitis, 117 in liver disease, 119–120
allergic bronchopulmonary, 339 Aspiration biopsy, in lung cancer, 359 Aspirin
in acute coronary syndrome, 145 in cerebrovascular accident, 411 in unstable angina/NSTEMI
management, 139 Aspirin (salicylate) toxicity, 386–387 Aspirin-sensitive asthma, 335
Astemizole, 435
Asthma, 334–338
Asystole, management of, 364 Atelectasis, 360
Atheroembolic disease, in acute renal failure, 289
Atherosclerosis, in end-stage renal disease, 299
Atlantoaxial subluxation, 67, 68
Atopic asthma, 335
Atopic dermatitis, 451–452
Atrial dysrhythmias, 369–373 Atrial fibrillation (A-fib), 179–183,
369–373
management algorithm, 181
patient evaluation, 182
Atrial flutter, 179, 369–373
Atrial tachycardia, 366, 370
multifocal, 179
Atrioventricular (AV) block, 176–178, 373–374
Atropine, contraindicated in asystole, 364 Autoimmune diseases
hemolytic anemia, 204–205
pemphigus vulgaris, 434
Autoimmune pancreatitis, 118 Automatic implantable cardioverter/
defibrillator (AICD), 161
Autonomic neuropathy, 46 Avian influenza, as pneumonia
predisposition, 239 Azathioprine, for inflammatory bowel
disease, 100 Azotemia
in acute renal failure, 282 postrenal, 284
prerenal, 282–284
“B” symptoms, of Hodgkin disease, 215, 216
B-type natriuretic peptide (BNP)
in congestive heart failure diagnosis, 154
in pleural effusion diagnosis, 331
Bacillus anthracis, as pneumonia predisposition, 239
Bacillus Calmette-Guérin (BCG) vaccination, 243
Bacillus cereus, infectious diarrhea and, 103
Background retinopathy, 46, 465 Baclofen
in ALS, 423
in multiple sclerosis therapy, 426 Bacterial infection. See also under
Infectious disease
brain abscess and, 232
endocarditis. See Infective endocarditis of skin, 441–443
Bacteriuria, in renal disease diagnosis, 298
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
475
USMLE Step 2 CK l Internal Medicine
Bacteroides infection, brain abscess and, 232 Baker cyst, 68
Barbiturates
clearance time, 378
overdose, 383
Barium studies, 461
in diffuse esophageal spasm, 88 esophagitis and, 89
in inflammatory bowel disease, 108 Barrett esophagus, 94
Bartter syndrome, 53 Basal cell carcinoma, 450 Basophilic stippling, 198
Below-the-knee DVT, 356 Bence-Jones protein
in acute renal failure, 288 in nephrotic syndrome, 296
Benedikt syndrome, 410 Benign essential tremor, 431
Benign paroxysmal positional vertigo, 416 Benzodiazepines
in alcohol withdrawal management, 390 clearance time, 378
overdose, 383
Berger disease, 294
Beta-adrenergic agonists for asthma, 336
for COPD, 341
Beta blockers
in acute coronary syndrome, 145 adverse effects, 189
as antihypertensive, 317
in asthma, 336, 337
atrial dysrhythmias and, 374
in cardiovascular disease, 189–190 in congestive heart failure, 155
in COPD, 341
in unstable angina/NSTEMI, 140 for ventricular fibrillation, 368
Beta-lactam antibiotics, 443
Beta-lactamase inhibitor, 227
Beta thalassemia, 199
Bi-level positive airway pressure (BiPAP), 333
Bicarbonate therapy
in barbiturate toxicity, 383 in salicylate toxicity, 386
in tricyclic antidepressant toxicity, 388 Biguanides (metformin), 41, 42
Binswanger disease, 427
Biologic agents, in RA management, 67
Bite injuries, 402–404
Biventricular pacemaker, 158 Bleeding
in end-stage renal disease, 299 evaluation algorithm, 219
gastrointestinal, 113–116 Blisters
in burn injuries, 397, 398
disease involving, 434–435
toxidromes and, 376 Blood products
in anemia management, 194
Bone marrow, radiation injury to, 400, 401 Bone marrow transplantation
allogenic, in acute leukemia, 210 in aplastic anemia, 209
autologous, in multiple myeloma, 213 in radiation injury management, 401
Bordetella pertussis, as pneumonia predisposition, 239
Brain imaging, in dementia assessment, 428 Brain natriuretic peptide. See B-type
Breast cancer
in males, hypogonadism and, 58 screening for, 2
Breast feeding, by HIV-positive patients, 278
BRIT mnemonic, 429 Bromocriptine
acromegaly and, 17
hyperprolactinemia and, 14, 15
Bronchietasis, 343–344
Bronchitis, 237 Bronchoalveolar lavage
in idiopathic pulmonary fibrosis, 346 in Pneumocystic jiroveci identification,
273
in Pneumocystis pneumonia diagnosis, 241
Bronchodilator reversibility, 324 Bronchodilators, in COPD, 342 Bronchogenic carcinoma, 358–360 Bronchopulmonary aspergillosis,
allergic, 339 Bronchoscopy
in burn injury assessment, 397 in lung cancer, 359
Brown-Séquard syndrome, 408 Bullae, necrotizing fasciitis and, 443 Bullous/blistering diseases, 434–435
Bullous pemphigoid, 434
Burn injuries, 396–398
C-11/C-17 hydroxylase deficiency, 52–53 Cabergoline
acromegaly and, 17
hyperprolactinemia and, 14, 15
CAGE questionnaire, 9
Calcinosis, in CREST syndrome, 71 Calcitonin
in calcium regulation, 35 in hypercalcemia, 33, 35
in primary hyperparathyroidism, 37 in thyroid carcinoma, 32
Calcium, regulation of, 33, 35 Calcium channel blockers
as antihypertensive, 317 atrial dysrhythmias and, 374 in cardiovascular disease, 190
Calcium hydroxyapatite (HA), 78–80 Calcium oxalate (CaOx), 78–80 Calcium pyrophosphate (CPPD), 78–80 Calymmatobacterium granulomatis
infection, 256
Campylobacter infection
Guillain-Barré syndrome and, 421 infectious diarrhea and, 102, 103, 104 reactive arthritis and, 75
Cancer. See specific cancers
Cancer screening, 1–3
Candida esophagitis, 89 Candidiasis, of skin, 440 Caplan syndrome, 349
Capsaicin cream, 78
Capsule endoscopy, 461
Captopril, for congestive heart failure, 155
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
476
Index
Carbamazepine
in seizure and epilepsy management, 414–415
in trigeminal neuralgia therapy, 420 Carbapenems, 228
Carbidopa/levodopa, 430
Carbohydrate metabolism, disorders and, 40–48
Carbon monoxide (CO) poisoning, 380–381
burn injuries and, 396
Carbon monoxide diffusing capacity (DLCo), 322, 324
Carboxyhemoglobin (COHb) levels in burn injuries, 397
in carbon monoxide poisoning, 380, 381
Carbuncles, 442
Carcinoid syndrome, 107 Cardiac biomarkers, in chest pain
evaluation, 127
Cardiac catheterization, in IHD, 136 Cardiac enzyme serum levels, in chest pain
evaluation, 127–128
Cardiac glycosides, 156–157 Cardiac output
oxygen delivery and, 326 in shock syndromes, 191
Cardiac resuscitation, in cardiac dysrhythmias, 364–375. See also Cardiopulmonary resuscitation (CPR)
Cardiac tamponade, 173–174 Cardiac troponins, in chest pain
evaluation, 127–128
Cardiogenic shock, 190, 191 Cardiology
acute coronary syndrome, 137–149 arrhythmias, 176–187
chest pain evaluation, 125–128.
See also Angina congestive heart failure, 150–159 ischemic heart disease, 130–137 myocardial disease, 168–171 non-ST elevation myocardial
infarction, 137, 138–140 nonatherosclerotic coronary
syndrome, 148–149
patient history, 125–126
pericardial disease, 172–175
rate and rhythm disturbances, 176–187 shock syndromes, 190–191
ST elevation myocardial infarction, 140–146
valvular heart disease, 160–167 Cardiomyopathy
dilated (congestive), 158, 168–169
hypertrophic obstructive, 169–171 morphologic and hemodynamic
characteristics, 168
restrictive, 171 Cardiopulmonary arrest, pulseless,
management algorithm for, 187, 363
Cardiopulmonary resuscitation (CPR) in ACLS management algorithm,
187, 363
in basic life support, 361–363 in children, 362
in pulseless electrical activity, 368–369 Cardiovascular disease
as chest pain cause, differential diagnosis, 129
diabetes mellitus and, 45 drug therapies for, 188–190 hypercalcemia and, 34
hypertension and, 312, 315 Cardioversion therapy
in atrial dysrhythmias, 373 in atrial fibrillation, 182
in ventricular fibrillation, 365 in ventricular tachycardia, 368
infective endocarditis, 263–270
myocarditis, 129, 130, 271 Caregivers, of dementia patients, 428 Carotid angioplasty, 411
Carotid endarterectomy, 411 Carotid sinus massage, for atrial
dysrhythmias, 371
Carpal tunnel syndrome, in acromegaly, 16 Caspofungin, 280
Casts, in renal disease diagnosis, 298 Cat bites, 402–403
Cataracts, 470
Catecholamines, in pheochromocytoma, 56, 57
Cathartics, in toxic ingestion/overdose management, 377
Catheter ablation, in atrial fibrillation, 183
Caustics/corrosives, toxic exposure to, 381–382
CD4 cell count, in AIDS, 275–276 CD19, chronic lymphocytic leukemia
and, 211
CD55/CD59, paroxysmal nocturnal hemoglobinuria and, 207
Cefotaxime, 119
Ceftaroline, 227
Ceftriaxone, 119, 227
Celiac disease, 109
antibodies in, 108
Celiac sprue, 109 Cellulitis
periorbital, 471
of skin, 442
Central-acting sympatholytics, as antihypertensives, 317
Central diabetes insipidus (CDI), 19–21, 303
Central nervous system (CNS) infections, 228–233
lymphoma, 217
in salicylate toxicity, 386
Central retinal artery/vein occlusion, 468 Central sleep apnea, 358
Central venous lines, positioning for chest x-rays, 458
Central vertigo, 416 Cephalosporins
gram-negative bacilli and, 227 gram-positive cocci and, 226
Cerebral abscess, 232–233 Cerebral artery occlusion, 409–411 Cerebral contusion, 391, 393
Cerebrospinal fluid (CSF) analysis/culture in meningitis, 230
in multiple sclerosis, 425 Cerebrovascular accident (CVA), 409–411.
See also Stroke Cerebrovascular disease
cerebrovascular accident, 409–411
hypertension and, 313 Cervical cancer, screening for, 2
CHADS2/CHADS2-VASc score, in atrial dysrhythmias, 183, 372
Chancre, in syphilis, 253, 254
Chancroid, 254–255 Charcoal therapy
in acetaminophen toxicity, 379 contraindicated, 380
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
477
USMLE Step 2 CK l Internal Medicine
in digoxin toxicity, 387 in salicylate toxicity, 386
in toxic ingestion/overdose
management, 377
Chelation therapy, in lead poisoning, 384 Chemical stress testing, 135
Chest pain. See also Angina causes, 128–130
evaluation, 126–128
patient history and, 125–126 physical examination in, 126–127 quality, 126
testing in, 127–128
Chest physiotherapy, 343
Chest radiography. See Chest X-rays Chest tubes, positioning for chest x-rays,
458
Chest x-rays, 455–459
in adult respiratory distress syndrome, 357
air under diaphragm on, 458–459 in aortic regurgitation, 167
in asbestosis, 349
in asthma diagnosis, 336 basic principles of, 455–456
in burn injury assessment, 397 in chest pain evaluation, 128
in coal miner’s lung/coal worker’s pneumoconiosis, 349
common disorders seen on, 457–459 in congestive heart failure diagnosis, 154 in COPD, 342, 457
decubitus films, 456
expiratory films, 456 film quality of, 456
in heart failure diagnosis, 154 interstitial infiltrates, 327
lateral, 456
in lung cancer, 359
in mitral regurgitation, 161 in mitral stenosis, 161
in pleural effusion, 330, 331–332
in pleural effusion diagnosis, 331–332 in pneumoconiosis, 348
positioning lines and tubes for, 458 in pulmonary disease, 327–332
in pulmonary edema, 159 pulmonary nodule on, 328
in pulmonary thromboembolism, 352–353
in sarcoidosis, 347
in silicosis, 349
Chickenpox, 444 Children, CPR for, 362
Chlamydia psittaci, as pneumonia predisposition, 239
Chlamydia trachomatis lymphogranuloma venereum and, 255 urethritis and, 251–252
Chloroquine, 4
Cholangitis, primary sclerosis, 122 Cholesterol level
in diabetes mellitus, 45 in IHD, 131, 136
Chondroitin sulfate, osteoarthritis and, 78 Chorea, in Huntington disease, 428 Choreoathetoid movements, in Wilson
Chronic hypouricemic gout, 79 Chronic leukemia, 210–213
Chronic obstructive pulmonary disease (COPD), 339–343
chest x-rays in, 457 complications, 340
etiology/pathogenesis, 339–340
exacerbations, managing, 342–343 finger clubbing in, 340
physical examination/diagnosis, 340 pleural effusions in, 330–331 prognosis, 343
therapeutic approaches in, 341–343 Chronic pancreatitis, 108
Chronic suppressive therapy, genital herpes, 257
Churg-Strauss syndrome (CS), 82, 292–293
Chvostek sign, 39
Ciguatera-toxin, infectious diarrhea and, 103, 246
Cinacalcet, 37
Cirrhosis, primary biliary, 121 Cirrhosis of liver, 119
gastrointestinal bleeding and, 113, 121
hemochromatosis and, 122 CK-MB isoenzyme, in chest pain
evaluation, 127
Clindamycin, 227, 228
Clopidogrel, in acute coronary syndrome, 145
Closed-angle glaucoma, 469
Clostridial myonecrosis, 262
Clostridium difficile
diarrhea caused by, 105 infectious diarrhea and, 102
Clostridium septicum, 111
Clostridium tetani, 279
Cloxacillin, 225, 226
Clozapine, 428
Cluster headaches, 418
Coagulopathy, 220–224
Coal miner’s lung/coal worker’s pneumoconiosis (CWP), 349
Coarctation of aorta, 316 Cocaine
clearance time, 378
overdose, 382–383 Codeine, clearance time, 378
Cognitive function, dementia and, 426–427 Cold agglutinin hemolytic anemia, 204–206 Colon cancer, 111–113
screening for, 2, 112, 113 Colonoscopy
in colon cancer diagnosis, 112
in diverticular disease diagnosis, 110 as preventive medicine, 2
virtual, 462
Colony-stimulating factors (CSFs), in radiation injury management, 401
Common ALL antigen (CALLA), 209 Community-acquired pneumonia, 241
Complete heart block, 278, 373, 374
Complex seizures, 412 Computed tomography (CT)
in acute pancreatitis, 117–118 central nervous system and, 463 in cerebral abscess, 232
in cerebral artery occlusion, 409, 410 contrast agents for. See Contrast
agents, acute renal failure and
in head trauma, 392–394
high-resolution, of lung parenchyma, 459
in pulmonary embolism, 353–354
in subarachnoid hemorrhage, 395–396 COMT inhibitors, as Parkinson disease
therapy, 430
Concussion, 391, 392
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
478
Index
Conduction abnormalities, in acute coronary syndrome, 146
Congenital adrenal hyperplasia (CAH), 52–53
Congestive heart failure (CHF), 150–159 case examples, 150
chest x-rays in, 458 diagnosis, 154
inter-related cycles in, 151 management, 154–158
patient workup recommendations, 153 pleural effusions and, 329 precipitating factors in, 152
pulmonary edema in, 151, 153, 158–159
severity classification, 153
Conjunctival diseaes, 470–471
Conjunctivitis, 470
Conn syndrome, 316 Consciousness, loss of. See Syncope Constipation, 111
Constrictive pericarditis, 174–175
Contact dermatitis, 435, 452 Continuous positive airway pressure
(CPAP), 333, 334, 402
Contractility increase/reduction, in HOCM, 170
Contrast agents, acute renal failure and, 289 prevention, 290
Cooley anemia, 199
Cooling, rapid, as heat stroke therapy, 398 Coombs test
in autoimmune, cold agglutinin, and drug-induced hemolytic anemia diagnosis, 205
in hereditary spherocytosis diagnosis, 206
Copper, Wilson disease and, 122–123 Coronary angiography, in unstable angina/
NSTEMI, 140
Coronary artery bypass graft (CABG) in ischemic heart disease, 136–137 in STEMI, 144
Coronary atherosclerosis, myocardial infarction without, 149
Coronary heart disease. See Ischemic heart disease (IHD)
Corticosteroids
for asthma, 336–337
for COPD, 341–343
for meningitis, 231
for SLE, 69
Corticotropin-releasing hormone (CRH), 49–51
Costochondritis, as chest pain cause, 129 Cough, nocturnal, 335
Coumadin. See Warfarin Cowden syndrome, 113
Coxiella burnetti, 239, 242 Creatine kinase (CK), in chest pain
evaluation, 127
Creatinine clearance, in acute renal failure, 282
Crepitus, necrotizing fasciitis and, 443 CREST syndrome (limited scleroderma),
71–72
Creutzfeldt-Jakob disease (CJD), dementia secondary to, 427
Crohn disease (CD), 100–101 enteropathic arthropathy in, 76 hyperoxaluria with, 288
primary sclerosis cholangitis and, 122 Cromolyn sodium, 337
Cryoglobulinemia, 294–295 Cryptococcosis, in AIDS, 275 Cryptosporidia, infectious diarrhea and,
Crystal-induced arthropathies, 78–80 Crystals, acute renal failure and, 288 Cullen sign, 117
Cushing disease/syndrome, 49–51 secondary hypertension in, 316
Cyclooxygenase 2 (COX-2) inhibitors in osteoarthritis, 78
in peptic ulcer disease, 76 in RA management, 66
for nephrotic syndrome, 297 Cyclosporine, acute renal failure and,
289, 290
Cystinuria, 310
Cystitis, 298
Cysts, renal, 311
Cytokines, rheumatoid arthritis and, 65 Cytomegalovirus infection, in AIDS, 274 Cytotoxic drugs, for SLE, 69
D
D-dimer test, 354
Dabigatran, 372
Dalfampridine, 426
Daptomycin, 227
Dawn phenomenon, 47
de Quervain (subacute) thyroiditis, 30 Decay accelerating factor (DAF), 206, 207 Decompensated heart failure, 152 Decubitus film, chest x-ray, 456 Decubitus (pressure) ulcers, 453
Deep vein thrombosis (DVT). See also
Pulmonary embolism (PE) leg swelling in, 351
limited distal, 356
overview, 350
pulmonary thromboembolism and, 350–357
risk categories for, 351–352 Defibrillation, 365
Degenerative joint disease (DJD), joint aspiration in, 63
Delirium tremens (DT), 390 Demand ischemia, 133
Dementia, 426–428 Depression
acute coronary syndrome and, 147 Parkinsonism and, 430
Dermal-epidermal junction,
cellulitis and, 442 Dermatitis
atopic, 451–452
contact, 435, 452
papulosquamous, 451–453
seborrheic, 452
stasis, 452
Dermatitis herpetiformis, 108
Dermatographism, 435 Dermatology
acne, 454
bacterial infections, 441–443
benign/precancerous lesions, 447–448
bullous/blistering diseases, 434–435
decubitus ulcers, 453
drug eruptions/hypersensitivity, 435–438
fungal infections, 439–440
hair-related disorders, 453
malignant diseases, 448–450
parasitic infections, 445–446 scaling disorders/papulosquamous
dermatitis, 451–453 skin anatomy and, 433
toxin-mediated diseases, 446–447
viral infections, 443–445
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
479
USMLE Step 2 CK l Internal Medicine
Dermatomyositis, 83–84
Dermatophyte infections, 439, 440
Dermo-epidermal junction, 434 Dermopathy, in Graves’ disease, 26 Desensitization, urticaria and, 436 Desmopressin (DDAVP)
in hemophilia, 220
in von Willebrand disease, 219 Detachment, retinal, 466–467
DEXA scan, in osteoporosis screening, 8 Dexamethasone therapy, for meningitis, 231 Dextrose therapy, in toxic ingestion/
overdose management, 377 Diabetes insipidus
central and nephrogenic, 19–21, 303
hypernatremia and, 303
Diabetes mellitus, 40–47 Candida esophagitis in, 89 classification, 40
complications, 43–47
end-stage renal disease and, 298 glomerulonephritis and, 291, 295 as IHD risk factor, 132
screening for, 9
Diabetic ketoacidosis (DKA), 43–44 Diabetic nephropathy, 45–46
Diabetic neuropathy, 46–47
Diabetic retinopathy, 46, 465–466 Dialysis
for alcohol intoxication, 380
in end-stage renal disease, 298–300 for lithium poisoning, 386
for salicylate toxicity, 387 in toxic ingestion/overdose
management, 377 Diaphragm, air under, on chest x-rays,
458–459
Diarrhea
antibiotic-associated, 105–106 carcinoid syndrome and, 107 chronic, 104–105
infectious, 102–105, 246–248
irritable bowel syndrome and, 106–107 lactose intolerance and, 106
nocturnal, 105
traveler’s, 4, 104 Diastolic dysfunction
in congestive heart failure, 151, 158
in HOCM, 169
Dicloxacillin, 225, 226
Diet. See Lifestyle modification
Diffuse capillary leak, burn injuries and, 397 Diffuse esophageal spasm, 88
Digitalis
for congestive heart failure, 156–157 toxic effects, 157
Digoxin
drug interactions associated with, 157 toxicity, 387
Dilated (congestive) cardiomyopathy, 168–169
therapy for, 158, 169
Dipeptidyl peptidase (DPP-IV) inhibitors, for diabetes mellitus, 42
Diphtheria/tetanus (DT) vaccine, 5 Dipyridamole stress test, 135 Discoid lupus (DLE), 69
Disease-modifying agents in dementia, 428
acute leukemia and, 209 liver disease and, 119
Distal renal tubular acidosis, 308–309 Distributive shock, 190, 191
Diuresis. See Urine output Diuretics
for congestive heart failure, 155–156 lithium poisoning and, 385
Dizziness, 415–417
DMARD (disease-modifying anti- rheumatic drugs), 67–68
adverse effects, 67 Dobutamine stress test, 135 Dog bites, 402–403
Domestic violence, screening for, 10 Dopamine
hyperprolactinemia and, 15
Parkinsonism and, 430
Doppler echocardiography, in mitral valve prolapse, 164
Doppler ultrasound, in pulmonary embolism diagnosis, 354
Doxycycline, 104, 228
DPP-IV (dipeptidyl peptidase) inhibitors, 42 Dressler syndrome, 147
Drowning, 401–402
Drug abuse, overdose/toxicity
management in, 382–384
Drug-induced hemolytic anemia, 204–205 Drug-induced lupus erythematosus, 70 Drug reactions, dermatological, 435–438
erythema multiforme, 436–437
erythema nodosum, 438 fixed drug reaction, 438 morbilliform rashes, 436
Stevens-Johnson syndrome, 437 toxic epidermal necrolysis, 437–438 urticaria, 435–436
Drug therapies. See also specific drugs and therapeutic agents
for acute coronary syndrome, 144–145 acute renal failure caused by, 289–290 antihypertensives, 316–318
for asthma, 336–337
for cardiovascular disease, 188–190 for congestive heart failure, 154–158 for hypertension, 316–318
Dry drowning, 401
DUMBELSS syndrome, 389
Dumping syndrome, 99
Dyesthesia, in Guillain-Barré syndrome, 421 Dyslipidemia, in diabetes mellitus, 45 Dyspepsia, nonulcer, 99
Dysphagia, oropharyngeal vs. esophageal, 85 Dysplastic nevus, 448
Dyspnea, cardiac vs. pulmonary, 154 Dysrhythmias. See also Arrhythmias in acute coronary syndrome, 146
asystole, 364
atrial, 369–372
ischemia-related, 361, 364, 365, 367, 369
management of, 364–375
pulseless electrical activity, 368–369
in tricyclic antidepressant toxicity, 388 ventricular, 365–368
E
Eaton-Lambert myasthenic syndrome, 422 Echocardiography
in aortic regurgitation, 167
in congestive heart failure, 154 in ischemic heart disease, 136 in mitral regurgitation, 163
in mitral stenosis, 161
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
480
Index
Eczema, 451–453 Edema
pitting, in congestive heart failure, 153 pulmonary. See Pulmonary edema
Edrophonium (Tensilon) test, 422 Efavirenz, 278
Effusion
parapneumonic, 330
pericardial, 173–174 pleural. See Pleural effusion
Electrocardiogram (ECG)
in acute pericarditis, 172–173 in aortic regurgitation, 167 in asystole, 364
in atrial fibrillation, 179, 371
in atrial flutter, 179, 370 in atrial tachycardia, 370
in chest pain evaluation, 127 in complete heart block, 374
in congestive heart disease, 154
in congestive heart failure diagnosis, 154 in digoxin toxicity, 387
in first-degree heart block, 374 in hypothermia, 399
in ischemic heart disease, 134 in mitral regurgitation, 163 in mitral stenosis, 161
in myocardial infraction, 127 normal sinus rhythm on, 370 in NSTEMI, 142
in pulmonary edema, 159
in pulmonary thromboembolism, 353 in pulseless electrical activity, 368
in second-degree heart block, 177, 374
in STEMI, 141–142
in third-degree heart block, 178 in torsade de Pointes, 186, 367 in ventricular fibrillation, 365
in ventricular tachycardia, 367–368 Electroencephalogram (EEG), 413, 415 Electrolytes
changes in hypopituitarism, 18 in digoxin toxicity, 387
Electromyography (EMG), 422 Embolism, pulmonary. See Pulmonary
embolism (PE) Emergency, hypertensive, 315 Emergency medicine
anaphylaxis, 402
basic life support, 361–363 burn injuries, 396–398
drowning, 401–402
head trauma, 391–394
heat disorders, 398–399
radiation injuries, 400–401
subarachnoid hemorrhage, 394–396 toxicology, 376–391. See also Toxicology venomous bites and stings, 402–404
Emphysema, chest x-rays in, 457 Empty sella syndrome (ESS), 18–19
Enalapril, for congestive heart failure, 155 Encainide, adverse effects, 189 Encephalitis, 231–232
Encephalopathy, Wernicke, 390, 391 End-stage renal disease, 281
dialysis in, 298–300
for cerebrovascular accident, 411 Endocarditis
acute, embolic features of, 269 colon cancer and, 111
infective. See Infective endocarditis Libman-Sacks, 69
adrenal gland diseases, 48–57 carbohydrate metabolism disorders,
cholangiopancreatography (ERCP)
in acute pancreatitis, 116, 117
Endoscopic ultrasound, 460 Endoscopy
capsule, 461
in epigastric pain evaluation, 92
in gastroesophageal reflux disease, 93 in gastrointestinal bleeding evaluation,
116, 117
in inflammatory bowel disease diagnosis, 100
Endotracheal tubes, positioning for chest x-rays, 458
Entecavir, for hepatitis infection, 250 Enteropathic arthropathy, 74, 76
Eosinophilic esophagitis, 90
Epidural hematoma, 391, 393
Epigastric pain, 93–99
in Barrett esophagus, 94 in dumping syndrome, 99 in gastritis, 96–97
in gastroesophageal reflux disease, 93–94
in gastroparesis, 98
in nonulcer dyspepsia, 99 overview, 92
in peptic ulcer disease, 94–96
in Zollinger-Ellison syndrome, 97–98 Epilepsy, 411–415
Erectile dysfunction (ED)
acute coronary syndrome and, 148 in diabetes mellitus, 47
Erysipelas, 442
Erythema migrans rash (Lyme disease), 270–271
Erythema multiforme, 436–437 Erythema multiforme major, 437 Erythema nodosum (EN)
drug-induced, 438
in rheumatic disorders, 76 Erythrocyte sedimentation test (ESR), in
temporal arteritis, 83
Erythrocytosis, 340
Escherichia coli, infectious diarrhea and, 103, 104
Esophageal dysfunction, in CREST syndrome, 71
Esophageal dysphagia, 85
Esophageal varices, 114
Esophagitis, 89–90
Esophagogastroduodenoscopy (EGD), 93 Esophagus, diseases of, 85–91
achalasia, 86–87
cancer, 87–88
esophagitis, 89–90
Mallory-Weiss syndrome, 91
overview, 85
rings and webs, 89
Zenker diverticulum, 90–91
Essential hypertension, 312–313
Essential thrombocythemia, 213 Essential tremor
benign, 431
Parkinsonism vs, 430
Etanercept (Enbrel), 67
Ethambutol (ETB), 79, 244, 274
Ethanol-induced hypoglycemia, 48 Ethical issues, in ALS therapy, 423–424
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
481
USMLE Step 2 CK l Internal Medicine
Ethosuximide, 414
Ethylene glycol poisoning, 379–380 acute renal failure and, 288
Euvolemic states
in hyponatremia, 302
rate control in atrial dysrhythmias and, 372
Exchange transfusion, in sickle cell disease, 204
Exercise
asthma induced by, 335
lack of, as IHD risk factor, 132 Exercise stress test
in acute coronary syndrome, 146 in ischemic heart disease, 134–135
Exertional heat disorders, 398 Exophthalmus, 26
Expiratory film, chest x-ray, 456 Extracellular fluid (ECF), hyponatremia
and, 301
Extrinsic (allergic, atopic) asthma, 335 Exudative pleural effusion, 329
F
Factitious hyperinsulinism, 48
Factitious hyperthyroidism, 25
Factor VIII, 119
False-positive stress tests, 135 Familial adenomatous polyposis, 112 Familial hypocalciuric hypercalcemia
(FHH), 34
Faruncles, 442
Fasciitis, necrotizing, 442–443
Fasting hypoglycemia, 47
Fat embolism, 357
Feedback inhibition, pituitary gland and, 12 Fibrillation
atrial. See Atrial fibrillation (A-fib) ventricular, 365
Fibrinolytics. See Thrombolytics Fidaxomicin, 106
Finger clubbing, in chronic hypoxemia, 340 Fingolimod, 426
First-degree AV block, 176, 373, 374
First-degree burns, 397
Fistula, perilymphatic, 416 Fixed drug reaction, 438 Flecainide, adverse effects, 189 Flow volume loops, 325–326 Fluconazole, for esophagitis, 89
Fluid/electrolyte disorders hyperkalemia, 304–305
hypernatremia, 303
hypokalemia, 304
hyponatremia, 300–302
renal disease, 300–305
SIADH, 302–303
Fluid resuscitation/replacement, in burn injury, 397
Fluorescent antinuclear antibody (FANA) test, 63
Fluoroquinolones, 227
Focal-segmental glomerulosclerosis (FSGS), 297
Folic acid deficiency, 201
Follicle-stimulating hormone (FSH) hyperprolactinemia and, 14
hypopituitarism and, 17 Follicular carcinoma, of thyroid, 32 Folliculitis, 442
Food poisoning, 246–248 Foot ulcer, diabetic, 46
Forced diuresis, in toxic ingestion/ overdose management, 377
Forced expiratory volumes (FEVs) as COPD prognostic factor, 343
in pulmonary function testing, 323
Francisella tularensis, as pneumonia predisposition, 239
G
Gait, in Huntington disease, 428 Galactorrhea, in hyperprolactinemia, 14 Gallbladder, HIDA scanning of, 461–462 Gallbladder disease, as chest pain cause, 129 Gallstone pancreatitis, 116, 117
Gamma glutamyl transpeptidase (GGTP), 121
Gangrene, gas, 262
Gardner syndrome, 113
Gas chromatography/mass spectrometry, in toxicology screen, 378
Gas exchange disturbances, 326–327 in asthma, 335–336
Gas gangrene, 262
Gastric lavage
in hypothermia management, 399 in toxic ingestion/overdose
management, 377, 382, 385 Gastrin-producing cells, cancer of. See
Zollinger-Ellison syndrome
(ZES)
Gastrinomas. See Zollinger-Ellison syndrome (ZES)
Gastritis, 96–97 Gastroenterology
acute pancreatitis, 116–118
colon cancer, 111–113
constipation, 111
diarrhea, 102–107
diverticular disease, 110–111 epigastric pain, 92–99. See also
Epigastric pain
esophageal disease, 85–91
gastrointestinal bleeding, 113–116 inflammatory bowel disease, 100–101 liver disease and cirrhosis, 119–123 malabsorption syndromes, 108–109 peptic ulcer disease, 94–96
Gastroesophageal reflux disease (GERD), 93–94
Barrett esophagus and, 94 as chest pain cause, 129
esophageal eosinophilia and, 90 Gastrointestinal bleeding, 113–116 Gastrointestinal tract
disorders of, chest pain and, 130 hypercalcemia and, 34
infection of, 246–248 radiation injury to, 400
Gastroparesis, 98
in diabetes mellitus, 46–47 Generalized seizures, 412
Genital infections, 251–257
chancroid, 254–255
granuloma inguinale, 256
herpes virus, 257
lymphogranuloma venereum, 255–256 primary chancre of syphilis, 253
warts, 257
Giant cell arteritis. See Temporal arteritis Giant cells, multinucleated, 443
Giardia, infectious diarrhea and, 103, 104
Glatiramer acetate therapy, 425, 426
Glaucoma, 469–470
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
482
Index
Glomerular filtration rate (GFR), 281, 282–288
Glomerulonephritis (GN), 291
causes, 291, 292
disease spectrum in, 291–297. See also specific diseases
Glucagon-like peptide (GLP), 42 Glucocorticoids
in multiple sclerosis, 425
in myasthenia gravis therapy, 422 in RA management, 67
Glucosamine, osteoarthritis and, 78 Glucose-6-phosphate dehydrogenase
(G6PD) deficiency, 207–208 Glucose tolerance, in acromegaly, 16 Glycoprotein IIb/IIIa inhibitors
for STEMI, 145
for unstable angina/NSTEMI, 140
Glycosylated hemoglobin A1c, 41 Goiter
in thyroiditis, 31
toxic diffuse (Graves’ disease), 25, 26–28 toxic multinodular (Plummer disease),
25
293, 324, 357
Gottron’s papules, 84
Gout, 78–80
chronic hypouricemic, 79 joint aspiration in, 62–63
Gram-negative bacilli, antibiotics for, 227–228
Gram-positive cocci, antibiotics for, 225–227 Gram stain, joint aspiration and, 62 Grand mal (tonic-clonic) seizures, 412 Granuloma inguinale, 256
Graves’ disease, 25, 26–28
Greenfield filter, 356
Griseofulvin, 439 Growth hormone (GH)
acromegaly and, 15–16
hypopituitarism and, 18
Guillain-Barré syndrome (GBS), 420–421 Gumma, in syphilis, 253
Gynecomastia, 58
H
Haemophilus ducreyi, 254
Haemophilus influenzae, 239
Hair-related disorders, 453 Hairy cell leukemia (HCL), 211 Hallucinogen overdose, 383
Hallucinosis, alcoholic, 390
Haloperidol, 428
Hampton hump, 353
Hashimoto disease/thyroiditis, 17, 25, 28,
30, 31
Head
infections, 233–236
trauma to, 391–394
Headache, 417–419
brain abscess and, 232
in carbon monoxide poisoning, 380, 381 Heart failure (HF). See also Congestive
compensatory mechanisms during, 151 decompensated, 152
with preserved ejection fraction, 151 systolic. See Systolic dysfunction, in
Heart sounds, abnormal, chest pain syndromes and, 126
Heerfordt-Waldenstrom syndrome, 347
Helicobacter pylori epigastric pain and, 92 gastritis and, 96–97
peptic ulcer disease and, 95, 96
Hematemesis, 113 Hematology
acute leukemia, 209–210
anemia, 193–195
aplastic anemia, 208–209
chronic leukemia, 210–213
coagulopathy, 220–224
hemolytic anemia, 201–208
lymphoma, 214–217
macrocytic anemia, 200–201
microcytic anemia, 196–199 plasma cell disorders, 213–214 platelet disorders, 218–219
Hematomas, in head trauma, 391–394 epidural, 393
subdural, 392, 393, 394
Hematuria
microscopic, in sickle cell disease, 203 in renal disease diagnosis, 298
Hemochromatosis, 122
Hemodynamic instability, in ventricular tachycardia, 368
Hemoglobin
acute renal failure and, 287–288 oxygen delivery and, 326
Hemolytic anemia, 201–208. See also specific forms
Hemolytic uremic syndrome (HUS), 222–223
Hemophilia A and B, 220 Hemorrhage
retinal, 468
subarachnoid. See Subarachnoid hemorrhage (SAH)
subconjunctival, 471 Hemorrhagic pleural effusions, 330 Hemosiderinuria, 207
Henoch-Schönlein purpura, 292, 294 Heparin, for pulmonary
thromboembolism, 355 Heparin-induced thrombocytopenia and
thrombosis (HITT), 223 Heparin-induced thrombocytopenia
(HIT), 223
in pulmonary thromboembolism, 355 Hepatitis
acute, 248–251
chronic, 123–124 comparative features in, 249
Hepatitis A virus
acute infection, 248–251
vaccine, 3, 6 Hepatitis B virus
acute infection, 248–251
chronic infection, 248 liver disease and, 123–124 needlestick injury, 251
in polyarteritis nodosa, 82 vaccine for, 3, 5
Hepatitis C virus
acute infection, 248–251
chronic infection, 248 liver disease and, 123–124
Hepatitis D virus, 248–251 Hepatitis E virus, 248–251 Hepatitis G virus, 248–251 Hepatorenal syndrome, 283
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
483
USMLE Step 2 CK l Internal Medicine
Hereditary cystic disease, 311 Hereditary nonpolyposis syndrome, 112
Hereditary polyposis syndromes, 112–113 Hereditary spherocytosis, 206
Heredity, as IHD risk factor, 133 Herniation
hiatal, as chest pain cause, 129
spinal cord compression and, 405–406 Heroin, clearance time, 378
Herpes, genital, 257 Herpes simplex infection
keratitis, 471
of skin, 443–444
Herpes zoster/varicella infection, 444 vaccine, 7
Hiatal hernia, as chest pain cause, 129 HIDA scanning, 461–462
High-resolution computed tomography, of lung parenchyma, 459
Highly active antiretroviral therapy (HAART), 278
Histamine blockers
in gastroesophageal reflux disease, 94 in peptic ulcer disease, 75
in Zollinger-Ellison syndrome, 98
Histoplasma capsulatum, as pneumonia predisposition, 239
Hives, in urticaria, 435 Hodgkin disease, 214–216
adverse prognostic factors in, 215 staging in, 215
Home oxygen therapy, for COPD, 341 “Honeymoon” period, in IDDM, 47 Horner syndrome, 410
Hospital-acquired pneumonia, 242 Hospitalization
asthma patients, 337–338 discharge recommendations,
in ACS, 145
for persistent hypoxemia, 332 “H’s and T’s” of dysrhythmia
management, 364
Human bites, 403
Human immunodeficiency virus (HIV).
See also Acquired immune deficiency syndrome (AIDS)
Candida esophagitis and, 89 management in pregnant patients, 278 rheumatoid arthritis and, 65
Human papillomavirus (HPV) genital warts caused by, 257 vaccine for, 7
Huntingtin protein, 428
Huntington disease, 428–429 Hyaluronic acid, for osteoarthritis, 78
Hydralazine, for congestive heart failure, 155 Hydrocephalus, normal pressure, 427 Hydromorphone, clearance time, 378 Hydroxychloroquine, in RA management, 67 Hydroxyurea, in sickle cell disease, 204 Hyperaldosteronism
amiodarone-induced, 29 secondary hypertension in, 316
Hypercalcemia, 33–35
acute renal failure and, 288 MEN-1 and, 97
Hypercalciuria, 310
Hypercarbia, in drowning victims, 401 Hypercholesterolemia, screening for, 9 Hyperinsulinism, 47
factitious, insuloma vs., 48 Hyperkalemia, 304–305
Hyperosmolar nonketotic coma (HONK), 45
Crohn disease and, 288 Hyperparathyroidism
Hyperphosphatemia, in end-stage renal disease, 299
Hyperpigmentation, in Addison disease, 54 Hyperprolactinemia, 13–15 Hypersensitivity, dermatological disease
and, 435–438
Hypertension (HTN)
in end-stage renal disease, 298, 299
essential, 312–313
glomerulonephritis and, 291 as IHD risk factor, 132 malignant, 314
medications for treating, 316–318 portal, in liver disease, 119 resistant, 315
screening for, 9, 315
secondary, 313, 315–316
Hypertensive emergency, 312, 315
Hyperthyroidism (thyrotoxicosis), 25–28, 30
Hypertonicity, in diabetes insipidus, 20 Hypertrophic obstructive cardiomyopathy
(HOCM), 169–171
in aortic stenosis differential diagnosis, 165
effect of maneuvers in, 166 morphologic and hemodynamic
characteristics, 168 Hypervolemic states, in hyponatremia, 301 Hypoaldosteronism, 309–310
Hypocalcemia, 38
in end-stage renal disease, 299 Hypocitraturia, 310
Hypoglycemia, 47–48
carbon monoxide poisoning vs., 381 Hypogonadism, 57–58
Hypokalemia, 304
digoxin poisoning and, 387
in vitamin B12 deficiency, 201 Hyponatremia, 300–302
Hypoparathyroidism, 38–39
Hypopituitarism, 17–18 Hyporeninemic renal tubular acidosis,
309–310
Hypothalamic-pituitary axis (HPA), pituitary gland diseases and, 11–12
Hypothalamus, 11–12
Hypothermia, 399–400
in drowning victims, 401 therapeutic, post-resuscitation care
and, 365
Hypothyroidism, 28–30
Hypouricemic therapy, 79 Hypoventilation
renal acidosis and, 308 respiratory acidosis and, 308
Hypovolemic shock, 191
Hypovolemic states, in hyponatremia, 301 Hypoxemia
chronic, finger clubbing in, 340
in COPD, home oxygen therapy for, 341 persistent, hospital admissions and, 332
Hypoxia, in drowning victims, 401
I
I STUMBLE (mnemonic), hemodialysis and, 377
Ice water immersion
as heat stroke therapy, 398
for supraventricular tachycardia, 371
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
484
Index
Idiopathic pulmonary fibrosis (IPF), 346 Idiopathic rapidly progressive
glomerulonephritis (RPGN), 295–296
Idiosyncratic asthma, 335
Imaging studies. See specific imaging modalities
Imatinib, 210–211
Immune system, monitoring in AIDS, 276–277
Immune thrombocytopenic purpura (ITP), 218
Immunizations, 4–7. See also Vaccines Immunoglobulin A (IgA)
anti-tissue transglutaminase antibody, 108, 109
nephropathy, 294
Immunoglobulin E (IgE) mediation, in urticaria, 435
Immunoglobulin therapy
in Guillain-Barré syndrome, 422 in myasthenia gravis, 422
Impetigo, 441
Implantable cardioverter/defibrillator (AICD), 158
Inclusion body myositis, 83–84 Incretin mimetics, 41–42
Infectious diarrhea, 102–105, 246–248 Infectious disease
acquired immunodeficiency syndrome, 273–278
antibiotics for, 225–228
aspergillosis, 279–280
asthma in, 335
of bone and joint, 260–262 carditis, 263–270
of central nervous system, 228–233 diarrhea, 102–105, 246–248
in end-stage renal disease, 299 gastrointestinal, 246–248
genital infections, 251–257
glomerulonephritis (postinfection), 294 Guillain-Barré syndrome and, 421
of head and neck, 233–236
hepatic (acute viral), 248–251. See also
Hepatitis entries
of lung, 237–245
Lyme disease, 270–271
nephrolithiasis and, 311
Q-fever, 239, 242
Rocky Mountain spotted fever, 272 sexually transmitted diseases, 251–257 of skin, 439–446
tetanus, 279
toxoplasmosis, 232, 233, 274–275 urinary tract infections, 258–260
Infective endocarditis, 263–270
acute, 265
bacterial, prevention of, 269–270 complications, 267
diagnostic criteria, 267
embolic features, 269
manifestations, 266–267 microorganisms responsible for, 265 risk factors for, 263–264
surgical criteria for, 268 treatment for, 267–268
Inflammatory diseases, hypopituitarism and, 17
Inflammatory myopathies, 83–84
carbon monoxide poisoning vs., 381 vaccine for, 5
(IDDM), 40
“honeymoon” period in, 47 Insulin-like growth factor (IGF), in
acromegaly, 16
Insulin therapy, 42
preparations, 43
Insulinoma, 47
Intensive care unit (ICU), persistent hypoxemia and, 332
Interferon gamma release assay (IGRA), 245 Interferons, in multiple sclerosis therapy,
425
International Normalized Ratio (INR), 224 Interstitial lung diseases (ILD), 345–349
chest x-ray, 327
Interstitial syndromes, of lung, 457 Intertriginous infections, 440 Intracranial hemorrhage, headache with,
417
Intrinsic asthma, 335 Intrinsic thyroid autonomy,
hyperthyroidism and, 25
Invasive aspergillosis, 280
Invasive ventilation, 333–334 Iodine therapy
for Graves’ disease, 28 hypothyroidism and, 28 thyroid storm and, 28
Ionizing radiation, injury from, 400 Ipecac, 377
Iron deficiency anemia, 196 in celiac sprue, 108
iron indices in, 199
Iron indices, in microcytic anemias, 199 Iron malabsorption, 108
Irrigation
following caustics/corrosives exposure, 382
whole bowel, in toxic ingestion/ overdose management, 377
Irritable bowel syndrome (IBS), 106–107 Ischemic heart disease (IHD), 130–137
acute coronary syndrome and, 147 risk factors for, 131–133
Isoniazid (INH), for tuberculosis, 244 Isopropyl alcohol ingestion, 380 Isosorbide dinitrate, for congestive heart
failure, 155
Isospora, infectious diarrhea and, 103, 104 Itraconazole, for fungal infections, 439 Ixodes scapularis, 270
J
J-wave, in hypothermia, 399
Janeway lesions, in infective endocarditis, 267
Joints
aspiration, in rheumatologic disease evaluation, 62–63
osteoarthritis and, 77
Jugular venous pressure (JVP), in congestive heart failure, 151, 152
Juvenile polyposis syndrome, 112
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
485
USMLE Step 2 CK l Internal Medicine
K
Kaposi sarcoma, 450
Kartagener syndrome, 344
Kayser-Fleisher rings, in Wilson disease, 122, 123
Keratitis, herpes simplex, 471 Keratoderma blennorrhagica, 76 Keratosis
actinic, 448
seborrheic, 447–448
Kidney. See also Renal function and disease; Renal entries
ACE inhibitor effects on, 283 stones. See Nephrolithiasis transplantation of, 300
Kimmelstiel-Wilson syndrome, 46
Klebsiella, as pneumonia cause, 239, 240
Klinefelter syndrome, 58
Koebner phenomenon, 451
KOH test, 439, 440
Korsakoff psychosis, 390, 391
Kussmaul respiration/sign, 44, 171, 174
L
Labyrinthitis, 416, 417
Lactate dehydrogenase (LDH), in pleural effusion diagnosis, 329
Lactose intolerance, 106
Lamivudine, acute viral hepatitis and, 250 Lamotrigine, for seizures and epilepsy,
414–415
Lanreotide, acromegaly and, 13 Large-cell carcinoma, of lung, 359
Laryngospasm, dry drowning and, 401 Lateral chest x-rays, 456
Lavage. See Bronchoalveolar lavage; Gastric lavage
Lead poisoning, 384 basophilic stippling in, 198
Ledipasvir/sofosbuvir (Harvoni), 124,
250, 251
Leg raising, effect on systolic murmurs, 166 Leg swelling, unilateral, in DVT, 351 Legionella, as pneumonia cause, 239, 240 Lesions, benign vs. malignant, 447 Leukemia
acute, 209–210
chronic, 210–213
Leukemoid reaction, 210
“Leukostasis” syndrome, 209 Leukotriene modifiers, for asthma, 337
Levetiracetam, for seizures and epilepsy, 414, 415
Levothyroxine (T4), 30, 31, 32 Lewy bodies, dementia with, 427
Libman-Sacks endocarditis, 69 Lidocaine
adverse effects, 189
for ventricular tachycardia, 368 Lifestyle modification
in diabetes mellitus, 41, 45
in end-stage renal disease, 299 in GERD management, 94
in hypertension management, 313 Limited distal DVT, 356
Limited scleroderma (CREST syndrome), 57–58
Lipase test, in acute pancreatitis, 117 Lipid management
for secondary prevention of IHD, 136 Lipid testing, in diabetes mellitus, 45 Lisinopril, for congestive heart failure, 155 Listeria monocytogenes, 229
Lithium/Lithium poisoning, 385–386 acute renal failure and, 290
Liver biopsy, primary sclerosis cholangitis and, 122
hepatorenal syndrome, 283 primary biliary cirrhosis, 121 primary sclerosis cholangitis, 122
serum-ascites albumin gradient and, 120 Wilson disease, 122–123
“Locked-in” syndrome, 410
Löfgren syndrome, 347 Loop diuretics
as antihypertensive, 316
in congestive heart failure, 156 Loss of consciousness. See Syncope Low molecular-weight heparin
(LMWH), for pulmonary thromboembolism, 355
Lower esophageal sphincter (LES) achalasia and, 86
in GERD, 93
Lumbar puncture
in meningitis, 230
in subarachnoid hemorrhage, 396 Lung
interstitial diseases of, 327, 345–349 interstitial syndromes of, 457
Lung cancer, 358–360
screening for, 2, 360
Lung infections, 237–245
abscess, 237–238
bronchitis, 237
pneumonia, 238–242
tuberculosis, 243–245
Lung parenchyma, imaging tools for, 459 Lung volumes, in pulmonary function
testing, 321, 322–323
Lupus anticoagulant, 65 Lupus erythematosus
drug-induced, 70
systemic. See Systemic lupus
erythematosus (SLE) Lupus nephritis, 70
Lupus pernio, 347 Luteinizing hormone (LH)
hyperprolactinemia and, 14
hypopituitarism, 17
Lyme disease, 270–271
Lymphocytic thyroiditis, 31
Lymphogranuloma venereum, 255–256
Lymphomas, 214–217
Lynch syndrome, 112
Macroadenomas, anterior pituitary, 13 Macrocytic anemia, 200–201
etiology, 193
Macrolides, 227
Macular degeneration, age-related, 467–468
Magnesium therapy, for ventricular fibrillation, 368
Magnetic resonance imaging (MRI) of brain, in multiple sclerosis, 425 central nervous system and, 463
Malabsorption syndromes, 108–109
Malar rash, 62, 69 Malaria, prophylaxis for, 3
Malassezia furfur infection, of skin, 439 Malignant diseases, of skin, 448–450 Malignant hypertension, 314
Malignant hyperthermia, 399
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
486
Index
Mallory-Weiss syndrome, 91
Maltese cross shape, in urinalysis, 296 Mammography, in breast cancer
screening, 2 Mast cells
activation, in urticaria, 435 stabilizers, for asthma, 337
Mean corpuscular volume (MCV), anemia and, 193–194
Measles, mumps, rubella (MMR) vaccine, 6 Mechanical cardioversion, in atrial
fibrillation, 182 Mediastinoscopy, in lung cancer, 359 Medullary carcinoma, of thyroid, 32 Meglitinides, 42
Melanoma, 448–449
Memantine, 428 Membranoproliferative nephrotic
syndrome, 297
Membranous nephrotic syndrome, 297 Memory loss, head trauma and, 391 Ménière disease, 416
Meningitis, 228–231
Meningococcal vaccine, 4, 6
Mercaptopurine (6MP), for
inflammatory bowel disease, 100 Mesalamine, for inflammatory bowel
disease, 100
Mesangial nephrotic syndrome, 297 Mesothelioma, pleural/peritoneal, 349
Metabolic acidosis, 306–307
Metabolic alkalosis, 305–306 Metacarpophalangeal (MCP) joints,
osteoarthritis in, 122 Metered dose inhalers (MDIs),
for asthma, 336
Metformin (biguanides), 41, 42
Methacholine challenge test, 322, 324 Methadone, clearance time, 378 Methanol poisoning, 379–380
Methicillin-resistant Staphylococcus aureus
(MRSA), 226, 227
hospital-acquired pneumonia and, 238 skin MRSA, antibiotics for, 228
Methimazole, for hyperthyroidism, 27 Methotrexate (MTX), in RA management,
67
Metronidazole, 228
for diarrhea, 105–106 Mexilitine, adverse effects, 189
Microadenomas, of anterior pituitary, 13
Microalbuminuria, 46
Microcytic anemia, 196–199
etiology, 193
iron indices in, 199 lead poisoning and, 384
Middle cerebral artery (MCA) occlusion, 409–410
Migraine headaches, 418
Migratory arthropathy, 61
Mild cognitive impairment, dementia and, 427
Mini Mental Status Examination (MMSE), 427
Minimal change disease, 297 Miosis, 376
Mitral regurgitation, 161–163 acute vs. chronic etiologies, 162
in aortic stenosis differential diagnosis, 165
effect of maneuvers in, 166 Mitral stenosis, 160–161 Mitral valve prolapse, 163–164
Mobitz I & II second-degree AV blocks, 177, 373, 374
Molluscum contagiosum, 444–445
Monoarticular symmetric involvement, in rheumatoid diseases, 61
Monobactams, 228 Monoclonal antibodies, in RA
Monoclonal gammopathy of uncertain significance (MGUS), 214
Mononeuropathy, 46 Monosodium urate (MSU), 78–80 Moraxella, 239
Morbilliform rashes, 436 Morphine, clearance time, 378 Movement disorders, 428–431 Mucosal-associated lymphoid tissue
(MALT), 97
Multi-infarct dementia, 427 Multifocal atrial tachycardia, 179 Multinodular goiter, toxic, 25 Multinucleated giant cells, 443 Multiple endocrine neoplasia
(MEN I and II)
RET mutations in, 32
thyroid medullary carcinoma and, 32 Zollinger-Ellison syndrome and, 97
Multiple myeloma, 213–214
Multiple sclerosis, 424–426 Mupirocin
for folliculitis, 442
for impetigo, 441 Murmurs
in aortic regurgitation, 167 chest pain syndromes and, 126
systolic, effect of maneuvers on, 166 Muscarinic effects, in organophosphate
poisoning, 389
Musculoskeletal disorders, chest pain and, 130
Myasthenia gravis, 421–422
Mycetoma, 280
Mycobacterium avium complex, in AIDS, 274
Mycobacterium tuberculosis, 243
Mycophenolate therapy, 423
for nephrotic syndrome, 297 for SLE, 69
Mycoplasma, as pneumonia cause, 239, 240
Mydriasis, 328
Myelodysplastic syndrome (MDS), 212 Myeloma, multiple, 213–214 Myocardial disease, 168–171. See also
Cardiomyopathy
Myocardial infarction (MI)
with ST elevation. See ST elevation myocardial infarction (STEMI)
without coronary atherosclerosis, 149 without ST elevation, unstable angina
and, 137, 138–140
Myocardial ischemia, in IHD, 133 Myocardial perfusion imaging, 146 Myocarditis, 271
chest pain and, 129, 130 Myoglobins
in acute renal failure, 287–288 in chest pain evaluation, 128
Myopathies, inflammatory, 83–84 Myotomy, for achalasia, 87 Myxedema, pretibial, 25
Myxedema coma, 30
N
N-acetyl cysteine (NAC), for
acetaminophen toxicity, 379
Nafcillin, 225, 226
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
487
USMLE Step 2 CK l Internal Medicine
Naloxone, in toxic ingestion/overdose management, 377
Narrow complex tachycardia, 370
Nasal polyposis, aspirin-sensitive asthma and, 335
Natalizumab, 425
Near-drowning, 401
Neck infections, 233–236 Necrosis, in acute pancreatitis, 117 Necrotizing fasciitis, 442–443
Nedocromil, 337 Needlestick injury
hepatitis viruses and, 123, 248, 251
HIV and, 278
Neighborhood signs, vertigo and, 416
Neisseria gonorrhoeae
septic arthritis and, 261–262 urethritis and, 251–252
Neisseria meningitidis, 229
Nephritis, allergic interstitial, 286–287 Nephrogenic diabetes insipidus (NDI),
19–21, 303
Nephrolithiasis, 310–311 Crohn disease and, 288
Nephrology. See Renal function and disease
Nephropathy analgesic, 290
diabetic, 45–46
hypertension and, 312, 315 immunoglobulin A (IgA), 294
Nephrotic syndrome, 296–297
Neuralgia, trigeminal, 420 Neuroleptic malignant syndrome, 399
Neurologic disease, hypertension and, 315 Neurology
cerebrovascular accident, 409–411
dementia, 426–428
Guillain-Barré syndrome, 420–421
headache disorders, 417–419
Huntington disease, 428–429
hypercalcemia and, 34
movement disorders, 428–431
myasthenia gravis, 421–422 seizures and epilepsy, 411–415 spinal cord diseases, 405–406 vertigo and dizziness, 415–417
Neuromuscular disorders
amyotrophic lateral sclerosis, 423–424 hyperparathyroidism and, 36
hypoparathyroidism and, 39
multiple sclerosis, 424–426
myasthenia gravis, 421–422 Neuropathy, in diabetes mellitus, 46–47 Neurosyphilis, 230, 253
Nevus, dysplastic, 448
New York Heart Association Functional Classification (NYHA staging system), 153–154
sexual activity risk and, 148 Newborn, hypothyroidism in, 29 Nicotinic effects, in organophosphate
poisoning, 389 Nikolsky sign
in pemphigus vulgaris, 434
in Staphylococcal scalded skin syndrome, 447
in toxic epidermal necrolysis, 437 Nil lesion nephrotic syndrome, 297 Nimodipine, 396, 411
Nissen fundoplication, in gastroesophageal reflux disease, 93
in acute coronary syndrome, 146 in cardiovascular disease, 188
Nitrites, in renal disease diagnosis, 298 Nitroglycerin (NTG)
for congestive heart failure, 155 response to, chest pain and, 126 for unstable angina/NSTEMI, 140
Nitroprusside, for congestive heart failure, 155
Nocturnal desaturation, in COPD, 340 Nocturnal diarrhea, 105
Non-exertional heat disorders, 398
Non-Hodgkin lymphoma (NHL), 216–217 Non-insulin-dependent diabetes mellitus
(NIDDM), 40
Non-nucleoside reverse transcriptase inhibitors (NNRTIs), 277, 278
Non-ST elevation myocardial infarction (NSTEMI), unstable angina and, 137, 138–140
high-risk features in, 139 Nonatherosclerotic acute coronary
syndrome, 148–149 Noncardiogenic pulmonary edema, in
salicylate toxicity, 386 Nonendocrine tumors, in Cushing
syndrome, 49–51
Noninvasive ventilation (NIV), 333 Nonionizing radiation, injury from, 400 Nonproliferative retinopathy, 46, 465 Nonsteroidal antiinflammatory drugs
(NSAIDs)
acute renal failure and, 290 asthma and, 335
gout and, 79, 80
lithium poisoning and, 385 for migraine headaches, 418 for osteoarthritis, 78
peptic ulcer disease and, 76, 94 rheumatoid arthritis and, 66 for SLE, 69
Nonulcer dyspepsia, 99
Normal pressure hydrocephalus (NPH), 427 Normocytic anemia, 193
Nuclear medicine scan
in acute cholecystitis, 461 in osteomyelitis, 463
Nuclear stress test, in ischemic heart disease, 135
Nucleoside reverse transcriptase inhibitors (NRTIs), 277, 278
Nutcracker esophagus, 88 Nystagmus, vertigo and, 416
Obesity, as IHD risk factor, 132 Obstructive disease, pulmonary, 334–344.
See also Chronic obstructive pulmonary disease (COPD)
Obstructive shock, 191
Obstructive sleep apnea (OSA), 358 Occlusion, of central retinal vessels, 468 Octreotide, acromegaly and, 16 Odynophagia, 85, 89
Oligoarticular symmetric arthritis, 62 Onychomycosis, 439
Open-angle glaucoma, 469 Ophthalmology
cataracts, 470
conjunctival diseases, 470–471
glaucoma, 469–470
keratitis, 471
periorbital cellulitis, 471
retinal diseases, 465–469
uveitis, 471–472
Ophthalmopathy, in Graves’ disease, 26 Opiate overdose, 382
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
488
Index
Opioid analgesics, for migraine headaches, 419
Opportunistic infections, in AIDS, 273–275 Oral candidiasis (thrush), 440
Oral hypoglycemic drugs, 41–42 Organophosphate poisoning, 389
Oropharyngeal dysphagia, 85 Orthostasis, in gastrointestinal bleeding,
114, 115
Osborne wave, 399
Osler’s nodes, in infective endocarditis, 267 Osmolar gap, 380
Osmotic fragility test, 206 Osteoarthritis (OA), 62, 77–78
acromegaly and, 16 joint aspiration in, 62
in metacarpophalangeal joints, 122 Osteodystrophy, in end-stage renal disease,
299
Osteomas, 113
Osteomyelitis, 260–261 imaging studies in, 463
Osteophytes, 77, 122 Osteoporosis, prevention of, 8 Otitis media, 233
Outpatient setting, for asthma patients, 336 Oxacillin, 225, 226
Oxalate crystals, acute renal failure and, 288 Oxygen delivery (Do2), gas exchange
disturbances and, 326
Oxygen supply/demand, shock syndromes and, 190–191
Oxygen therapy in asthma, 336
in carbon monoxide poisoning, 381 in COPD, 341, 342
supplemental. See Supplemental oxygen therapy
Oxytocin, pituitary gland and, 11
P
P-R waves, in AV block, 374 Pacemaker placement
in atrial dysrhythmias, 374 digoxin poisoning and, 387
Pacing, transcutaneous vs. transvenous, 374 Pain
abdominal, lead poisoning and, 384 chest. See Chest pain
epigastric, 92–99. See also Epigastric pain
on swallowing, 89 Pancreatic B-cell tumor, 47 Pancreatic pseudocyst, 118 Pancreatitis
acute, 116–118
autoimmune, 118
chronic, 108 epigastric pain in, 92 gallstone, 116, 117
severe necrotizing, 117
Pap smear, in cervical cancer screening, 2 Papillary carcinoma, of thyroid, 32 Papillary necrosis, acute renal failure and,
Papulosquamous dermatitis, 451–453
dementia secondary to, 427 “Parkinson plus” syndromes, 429 Parkland formula, 397
Paroxysmal nocturnal hemoglobinuria (PNH), 207
Paroxysmal supraventricular tachycardia, 178–179
Partial prothrombin time (PPT) in antiphospholipid antibody
in coagulopathies, 220–223 prolonged, causes of, 220
Partial thromboplastin time (PTT), in coagulopathies, 220–224
Patent foramen ovale, thromboembolism in, 351
Pediculosis, 445–446 Pegvisomant, acromegaly and, 17
Pelvic inflammatory disease (PID), 252 Pemphigus vulgaris, 434
Penicillins
allergic cross-reactivity and, 226 for bacterial infections of skin, 441 gram-negative bacilli and, 227 gram-positive cocci and, 225–226 skin reactions to, 435, 436
Pentamidine, acute renal failure and, 290
Peptic ulcer disease, 94–96 as chest pain cause, 129
Percutaneous coronary intervention (PCI), 137, 144, 145
indication for, 140
Pericardial disease, 272–275
Pericardial effusion, 173–174 Pericarditis
acute, 272–273
acute coronary syndrome and, 147 chest pain and, 129
constrictive, 174–175
Perilymphatic fistula, 416
Perinephric abscess, 259–260
Periorbital cellulitis, 471
Peripheral neuropathy, 46
Peritoneal mesothelioma, 349 Peritonitis
as dialysis complication in end-stage renal disease, 299
spontaneous bacterial, 119–120 Petechiae, in infective endocarditis, 267 Petit mal (absence) seizures, 412
Peutz-Jeghers syndrome, 113
PHAILS (mnemonic), charcoal therapy and, 377
Pharmacologic cardioversion, in atrial fibrillation, 182
Pharyngitis, 235
Phencyclidine (PCP), clearance time, 378 Phenylephrine handgrip, effect on systolic
murmurs, 166 Phenytoin therapy
adverse effects, 189
for seizures and epilepsy, 414–415 Pheochromocytoma, 56–57
secondary hypertension in, 316 Philadelphia chromosome, 210 Phlebotomy, for hemochromatosis, 122 Phosphatidyl inositol glycan A (PIG-A),
207
Photosensitivity rash/reaction
in porphyria cutanea tarda, 435 in SLE, 62, 69
Physical activity. See Exercise Physical examination, in chest pain
evaluation, 126–127 Physical therapy, in osteoarthritis, 77 Pick disease, 427
Pigments, acute renal failure and, 287–288 Pill esophagitis, 89
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
489
USMLE Step 2 CK l Internal Medicine
Pitting edema, 153
Pituitary apoplexy, 17
Pituitary gland, 11–12
action, 13
adenomas, 13–17
anatomy, 12
diseases, 11–23
Pityriasis rosea, 452
Pityrosporum orbiculare, 439
Pityrosporum ovale, 452 Plasma cell disorders, 213–214
Plasma-to-urine osmolality, in diabetes insipidus, 20–21
Plasmapheresis
in Guillain-Barré syndrome, 421 as myasthenia gravis therapy, 422
Platelet disorders, 218–219
Pleural effusion, 328–332
in acute pancreatitis, 117 chest radiography in, 330
decubitus chest x-ray detecting, 456 Pleural mesothelioma, 349
Pleuritis, chest pain and, 130 Plummer disease, 25
Plummer-Vinson syndrome (PVS), 89 Pneumatic dilation, for achalasia, 87 Pneumococcal vaccination, 5, 242
Pneumoconiosis, 348–349
Pneumocystis jirovecii infection in AIDS, 273
as pneumonia cause, 239 Pneumocystis pneumonia (PCP), 240 Pneumonia, 238–242
chest x-rays in, 457–458 Pneumoperitoneum, 459 Pneumothorax, chest pain and, 130 Pneumovax, 4
Poison ivy, contact dermatitis and, 452 Polio vaccine, 4
Polyarteritis nodosa (PAN), 82, 293 Polyarticular symmetric involvement, in
rheumatoid diseases, 61 Polycystic kidney disease, 311 Polycythemia vera, 212–213
Polymyositis, 83–84 Porphyria cutanea tarda, 435
Portal hypertension, in liver disease, 119 Positive end-expiratory pressure (PEEP),
333–334
Positron emission tomography (PET), 462
Postantibiotic effect, in acute renal failure, 289
Postencephalic Parkinsonism, 429 Posterior-anterior (PA) chest x-rays, 455 Posterior cerebral artery (PCA) occlusion,
410
Posterior circulation syndromes, in cerebrovascular accident, 410
Posterior pituitary lobe, diseases of, 19–23 Postexposure prophylaxis, HIV and, 278 Postinfectious glomerulonephritis, 294
Postprandial hypoglycemia, 47
Postpubertal hypogonadism, 58
Postrenal azotemia, 282, 284
Postthrombotic syndrome, 356
Potassium hydroxide (KOH) test, 439, 440 Potassium-sparing diuretics
in congestive heart failure, 156 Pre-excitation syndrome. See Wolff-
Parkinson-White (WPW) syndrome
Prednisone, in immune thrombocytopenic purpura, 218
contraindicated antihypertensives in, 317
in HIV-positive patients, 278 in hypertensive patients, 314
propylthiouracil for hyperthyroidism in, 27
Preload increase/reduction, in HOCM, 170
Prerenal azotemia, 282–284 Pressure (decubitus) ulcers, 453 Presyncope, vertigo vs., 415 Pretibial myxedema, 25
Preventive medicine, 1–10 abdominal aortic aneurysm, 8 alcohol abuse, 9
cancer screening, 1–3 hypertension, diabetes, and
hypercholesterolemia, 9
immunizations, 4–7
osteoporosis, 8
smoking cessation, 9
travel medicine, 3–4
violence and injury, screening for, 10 Primary biliary cirrhosis, 121
Primary hyperaldosteronism, 52 secondary hypertension in, 316
Primary hyperparathyroidism, 33, 36–37, 38
Primary hyperthyroidism, 26
Primary hypothyroidism, 30
Primary progressive multiple sclerosis, 424 Primary sclerosis cholangitis, 122 Prinzmetal angina, 149
Probenecid, gout and, 79, 80 Procainamide, adverse effects, 189 Prolactin, hyperprolactinemia and, 14 Prolactinomas, 14
opportunistic infections in AIDS, 273–275
postexposure, HIV and, 278 traveler’s diarrhea and, 104
Propionibacterium acnes, 454 Propranolol
for hyperthyroidism, 27
for migraine headaches, 419 Propylthiouracil (PTU), for
hyperthyroidism in pregnancy, 27 Prostate screening, 2
Protease inhibitors
acute renal failure and, 290
as antiretroviral therapy, 277, 278
boosted, 278
Proteinuria, in renal disease diagnosis, 298 Prothrombin time (PT)
in coagulopathies, 220–223 in Crohn disease, 100 prolonged, causes of, 220
Proton-pump inhibitors (PPIs) for Barrett esophagus, 94
for gastroesophageal reflux disease, 93, 94
for peptic ulcer disease, 95–96
for Zollinger-Ellison syndrome, 98 Proximal renal tubular acidosis, 309 Prussian Blue stain, in sideroblastic
anemia diagnosis, 197
Pseudocyst, pancreatic, 118
Pseudogout, 80
joint aspiration in, 62–63
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
490
Index
Pseudohyperkalemia, 304
Pseudotumor cerebri, 419–420
Psoriasis, 451
Psoriatic arthritis, 74, 76
Psuedocalcemia, 38
Psychosis, Korsakoff, 390, 391 Pulmonary disease
adult respiratory distress syndrome, 357 asthma, 334–338
atelectasis, 360
chest pain in, differential diagnosis, 129 chest radiography in, 327–332
COPD, 339–343
diagnostic tests in, 321–326
gas exchange disturbances in, 326–327 interstitial lung diseases, 345–349 lung cancer, 358–360
obstructive, 334–344
pleural effusions, 328–332
pulmonary nodule, 328
pulmonary thromboembolism, 350–357
sleep apnea, 357–358
ventilation and, 333–334 Pulmonary edema
causes, 158–159
in congestive heart failure, 151, 153, 159 noncardiogenic, in salicylate
intoxication, 386 Pulmonary embolism (PE), 350. See also
Deep vein thrombosis (DVT) chest pain and, 129
general diagnostic concepts for, 354 management algorithm, 355
Wells’ criteria for, 352
Pulmonary function tests (PFTs), 321–326 in COPD, 340
Pulmonary indices, 323
Pulmonary nodule, 328
Pulmonary thromboembolism, 350–357. See also Deep vein thrombosis (DVT); Pulmonary embolism (PE)
acute coronary syndrome and, 147 Pulmonic stenosis, in aortic stenosis
differential diagnosis, 165 Pulmonology. See Pulmonary disease Pulse oximetry, in carbon monoxide
poisoning, 381
Pulseless arrest management algorithm, 187, 363
Pulseless electrical activity (PEA), 368–369
Pump dysfunction, in acute coronary syndrome, 147
Purified protein derivative (PPD), in tuberculosis testing, 244, 245
Pyelonephritis, acute bacterial, 259 Pyoderma gangrenosum, 76
Pyrazinamide (PZA), 244
Q
Q-fever, 239, 242 QRS complex
in atrial dysrhythmias, 369
in normal complex tachycardia, 370 systolic dysfunction and, 158
in torsade de Pointes, 186
in tricyclic antidepressant toxicity, 388 in ventricular fibrillation, 365
in ventricular tachycardia, 184, 185 QT interval
in ventricular tachycardia, 367 Quinidine, adverse effects, 189 Quinolones, 227–228
Quinupristin/dalfopristin, 227
Radiation injuries, 400–401 Radioactive iodine. See Iodine therapy Radiology
central nervous system visualization and, 463
chest x-rays. See Chest x-rays PET scanning, 462
Rapidly progressive glomerulonephritis (RPGN), idiopathic, 295
Rate and rhythm disturbances, cardiac, 176–187
Rate control
in atrial fibrillation, 182, 183, 371, 372
ventricular, 183
Raynaud disease, 71
Raynaud phenomenon, 71 in systemic sclerosis, 62
Reactive arthritis, 74, 75 Reed-Sternberg cell
Hodgkin disease and, 214, 215 non-Hodgkin lymphoma and, 216
Regurgitation aortic, 166–167
mitral. See Mitral regurgitation Reidel thyroiditis, 31
Reiter syndrome
keratoderma blennorrhagia in, 76 reactive arthritis and, 75
Relapsing remitting multiple sclerosis, 424, 425
Renal artery stenosis, 283
secondary hypertension in, 315–316 Renal biopsy, in glomerulonephritis, 291 Renal failure, contrast-induced, 291 Renal function and disease
acid/base disturbances, 305–308 acute renal failure, 281–290
in diabetes mellitus, 45–46 diagnostic testing for, 297–298 end-stage renal disease/dialysis,
298–300
fluid/electrolyte disorders, 300–305
glomerulonephritis, 291–297 hereditary cystic disease, 311 hypercalcemia and, 34
hypertension and, 312–318 lithium poisoning and, 385 nephrolithiasis, 310–311
renal insufficiency, 281
renal transplantation, 300 renal tubular acidosis, 308–310
Renal insufficiency. See Azotemia
Renal proteinuria, hypertension and, 313 Renal transplantation, 300
Renal tubular acidosis, 308–310 distal (type I), 308–309
hyporeninemic/hypoaldosteronism (type IV), 309–310
proximal (type II), 309
Reperfusion therapy, in STEMI, 143–144 adjuvant therapy with, 144–145
Reproductive organs, radiation injury to, 400
Residual volume (RV), 321, 323
Respiratory acidosis, 308
Respiratory alkalosis, 306
Respiratory function, in salicylate toxicity, 386
Respiratory injury, from smoke inhalation, 396, 397
Restless leg syndrome (RLS), 431
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
491
USMLE Step 2 CK l Internal Medicine
Restrictive cardiomyopathy, 171 morphologic and hemodynamic
characteristics, 168 Resuscitation
cardiac dysrhythmias and, 364–375 cardiopulmonary. See
Cardiopulmonary resuscitation (CPR)
of drowning victims, 401–402 fluids, in burn injury, 397
RET mutations, in thyroid neoplasia, 32 Retapamulin, 441
Retinal artery occlusion, central, 468 Retinal detachment, 466–467
Retinal hemorrhage, 468
Retinal vein occlusion, central, 468 Retinopathy
diabetic, 46, 465–466
hypertension and, 313, 315 Retrograde memory loss, head trauma
and, 391
Revascularization, in unstable angina/ NSTEMI, 140
Rewarming therapy, in hypothermia, 399 Rhabdomyolysis
in acute renal failure, 287–288 in malignant hyperthermia, 399
in neuroleptic malignant syndrome, 399 Rheumatoid arthritis (RA), 65–68 Rheumatoid factors (RFs), 64 Rheumatology
arthritis evaluation, 61–62
crystal-induced arthropathies, 78–80
drug-induced lupus, 70
erythema nodosum, 76
inflammatory myopathies, 83–84
osteoarthritis, 77–78
psoriatic arthritis, 76
rheumatoid arthritis, 65–68
scleroderma, 70–72
septic arthritis, 81
seronegative arthropathies, 73–76
Sjögren syndrome, 72–73
spondyloarthropathies, 73–76 systemic lupus erythematosus, 68–70 testing in, 62–65
vasculitis syndromes, 81–83
RhoGam™, 218
Rhythm disturbances. See also
Arrhythmias; Dysrhythmias control in atrial fibrillation, 182, 372
sinus node dysfunction, 176–185 torsade de Pointes, 186–187 ventricular fibrillation, 365
Ribavirin therapy, in rabies, 403
Rickettsia rickettsii, 272
Rifampin (Rif), for tuberculosis, 244 Rifaximin, 104
Right ventricular infarction, 147 Riluzole therapy, in ALS, 423 Ringer’s lactate, in burn injury
management, 397
Ritonavir, 278
Rituximab, 206, 218
Rivaroxaban, 372
Rocky Mountain spotted fever (RMSF), 272 meningitis and, 229
Roth’s spots, in infective endocarditis, 267 “Rule of nines,” in skin injury assessment,
Salicylate intoxication, 386–387
infectious diarrhea and, 102, 103, 104 reactive arthritis and, 75
Samter’s triad (aspirin-sensitive asthma), 335
SARS, as pneumonia predisposition, 239 Scabies, 445
Scalded skin syndrome, staphylococcal, 446–447
Scaling disorders, of skin, 451–453 Schatzki’s ring, esophageal, 89 Schilling test, 201
Schirmer’s test, 73
Schober test, 74
Sclerodactyly, in CREST syndrome, 71 Scleroderma, 70–72
esophageal involvement in, 88 shiny skin in, 71
Scleroderma renal crisis, 71 Scromboid poisoning, 103, 104
Seawater drowning, 401
Seborrheic dermatitis, 452
Seborrheic keratosis, 447–448
Second-degree AV block, 177, 373, 374
Second-degree burns, 397
Secondary hyperaldosteronism, 52
Secondary hyperparathyroidism, 38
Secondary hypertension, 313, 315–316 Secondary progressive multiple sclerosis,
424, 425
Seizure disorders, 411–415
toxin-elated seizure, 378 Selegiline, in Parkinson disease, 431 Semisynthetic penicillinase-resistant
penicillins, 225–226
Septic arthritis, 81, 261–262 joint aspiration in, 62–63
Seronegative arthropathies, 73–76 Serum ascites albumin gradient (SAAG),
120
Serum osmolality, in hyponatremia, 300 Severe necrotizing pancreatitis, 117
Sex, as IHD risk factor, 133 Sex hormones, IHD and, 133
Sexual activity, acute coronary syndrome and, 148
Sexually transmitted diseases (STDs), 251–257
Sheehan postpartum necrosis, 17
Shigella infection
infectious diarrhea and, 103, 104 reactive arthritis and, 75
Shingles vaccine, 7
Shock syndromes, 190–191 Sickle cell disease, 203–204 Sickle cells, 204
Sickle trait, 203
Sickledex screening test, 204 Sideroblastic anemia, 197–198
iron indices in, 199
Sigmoidoscopy, in colon cancer diagnosis, 112
Silicosis, 349
Simple cysts, 311
Simple seizures, 412
Sinus bradycardia, 176, 373, 374
Sinus node function, disorders of, 176 –185 Sinus tachycardia, 178
Sinusitis, 234–235
Sjögren syndrome, 62, 72–73 Skin
anatomy, 433
burn injuries to, 396–398 in scleroderma, 70, 71
toxidromes, physical findings in, 376 warfarin-induced necrosis, 356
Skin cancers, 448–450
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
492
Index
Skin infections bacterial, 441–443
fungal, 439–440
genital warts, 257
methicillin-resistant Staphylococcus aureus, 228
MRSA, antibiotics for, 228 viral, 443–445
Skull fracture, depressed, 393 Sleep apnea, 357–358
Slit-lamp examination, in Wilson disease, 122, 123
Small cell carcinoma, of lung, 359 Smoke inhalation injuries, 396 Smoking
COPD risk and, 340 as IHD risk factor, 132 lung cancer and, 358
Smoking cessation
as COPD management strategy, 341 as preventive medicine, 7–8
“Smudge cells,” 211
Snakebites, 404
Sofosbuvir/ledipasvir (Harvoni), 124, 250,
251
Somogyi effect, 47
Sonography, in abdominal imaging, 460 Sore throat, S. pyogenes and, 235 Spherocytosis, hereditary, 206
Spinal artery occlusion, anterior, 407 Spinal cord diseases
anterior spinal artery occlusion, 407 Brown-Séquard syndrome, 408
cord compression, 405–406
subacute combined degeneration, 407 syringomyelia, 406–407
Spine fractures, in ankylosing spondylitis, 74
Spironolactone, in congestive heart failure, 156
Splenectomy
in immune thrombocytopenic purpura, 218
vaccinations prior to, 4 Splenic vein thrombosis, in acute
pancreatitis, 117 Splinter hemorrhage, in infective
endocarditis, 267
Spondyloarthropathies, 73–76 Spontaneous bacterial peritonitis (SBP),
119–120
Squamous cell carcinoma of lung, 359
of skin, 449
Squatting, effect on systolic murmurs, 166 ST elevation myocardial infarction
(STEMI), 140–146
EKG tracings, 142
evolution, 143
localization, 143 ST segment
in acute pericarditis, 172–173 in ischemic heart disease, 135
STEMI. See ST elevation myocardial infarction (STEMI)
Stable angina
ischemic heart disease and, 133–137 Staphylococcal scalded skin syndrome
Staphylococcus/Staphylococcus aureus
infection antibiotics for, 441 brain abscess and, 232
infectious diarrhea and, 103 meningitis and, 229
methicillin-resistant. See Methicillin- resistant Staphylococcus aureus (MRSA)
as pneumonia predisposition, 239 in scalded skin syndrome, 446–447 septic arthritis and, 81
toxic shock syndrome and, 446 Stasis dermatitis, 452
Statins, in acute coronary syndrome, 146 Status epilepticus, 412
development of, 414
Steatorrhea, 108 Stenosis
aortic. See Aortic stenosis mitral, 160–161 pulmonic vs. aortic, 165
renal artery. See Renal artery stenosis Steroids
for inflammatory bowel disease, 100 for nephrotic syndrome, 297
peptic ulcer disease and, 94 for sarcoidosis, 348
Stevens-Johnson syndrome, 437 Stool studies, in inflammatory bowel
disease, 100
Strep throat, 235 Streptococcal bacteria
brain abscess and, 232 Gram-positive, 225 necrotizing fasciitis and, 442 pharyngitis and, 235
as pneumonia cause, 238–239
in postinfectious glomerulonephritis, 294
skin infections and, 441
Streptococcus bovis, 111, 113
Streptococcus pneumoniae, 229, 238–240 Stress, IHD and, 133
Stress testing, in IHD, 135–136 Stroke, 409–411
hypopituitarism and, 18 Subacute combined spinal cord
degeneration, 407
Subacute (de Quervain) thyroiditis, 25, 30–31
Subacute infective endocarditis, 266 Subarachnoid hemorrhage (SAH),
394–396
in cerebrovascular accident, 411 CT sensitivity in, 463 traumatic, 391
Subconjunctival hemorrhage, 471
Subdural hematoma, 391, 392, 393, 394 Sudden cardiac death, 147 Sulfasalazine, in RA management, 67
Sulfonylureas, for diabetes mellitus, 41, 42 Sun protection, for SLE patients, 69 Supplemental oxygen therapy
in asthma, 336
in COPD, 341, 342
Supply ischemia, 133
Supratherapeutic INR, 224
Supraventricular arrhythmias, 178–183 Supraventricular tachycardia (SVT), 185,
369–373
Surgery. See also Transplantation; specific procedures
mitral valve replacement, 161, 163 in necrotizing fasciitis, 442
in osteoarthritis, 78
in Parkinson disease, 431
in peptic ulcer disease, indications for, 96
in STEMI, 145
Swallowing
difficulty in, 85
pain on, 85, 89
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
493
USMLE Step 2 CK l Internal Medicine
Swan-Ganz catheterization, in ARDS, 357 Symptom-triggered therapy, in alcohol
withdrawal management, 390
Syncope
head trauma and, 392 seizure vs., 412
Syndrome of inappropriate secretion of ADH (SIADH), 22, 302–303
Synovial fluid analysis, 62–63 Syphilis, 252–254
Syringomyelia, 406–407
Systemic lupus erythematosus (SLE), 62, 68–70
antinuclear antibodies in, 64 glomerulonephritis and, 295
malar rash in, 62, 69
Systemic sclerosis (SSc), 62, 70–72 progressive, esophageal involvement
in, 88
Systolic dysfunction, in congestive heart failure, 151
agents lowering mortality in, 156 medical devices for, 158
Systolic murmur, effect of maneuvers on, 166
T
T lymphocytes, rheumatoid arthritis and, 65 Tabes dorsalis, in syphilis, 253
Tachycardia
atrial, 366, 370
narrow/wide complex, 370
with pulses, management algorithm for, 366
supraventricular, 185, 369–373 ventricular. See Ventricular tachycardia
(VT)
Telangiectasias, in CREST syndrome, 71 Telavancin, 227
Telbivudine, for hepatitis infection, 250 Telogen effluvium, 453
Temporal arteritis (TA), 83, 417 Tenofovir, for hepatitis infection, 250 Tension-type headache, 418
Terbinafine, 439
Terfenadine, 436
Tertiary hyperparathyroidism, 38
Testicular diseases, 57–58
Testosterone therapy, 58
Tetanus, 279
vaccine for, 5
Tetrabenazine, in Huntington disease, 428 Tetrahydrocannabinol (THC), clearance
time, 378
Thalassemia, iron indices in, 198–199 Thalassemia trait, 199
Theophylline
for asthma, 336, 337
for COPD, 341
Theophylline toxicity, in COPD, 342 Thiamine
for alcohol withdrawal-related syndromes, 391
in toxic ingestion/overdose
management, 377 Thiazide diuretics
for congestive heart failure, 155, 156
Third-degree (complete) AV block, 178 Thoracocentesis, 330
Thrombocythemia, essential, 213
Thrombocytopenia, heparin-induced, 223 in pulmonary thromboembolism, 355
Thrombocytopenic purpura immune, 218
Thromboembolic disease, 350–357. See also Deep vein thrombosis (DVT); Pulmonary embolism (PE)
acute coronary syndrome and, 147 Thrombolytics
antithrombin therapy with, 145 NSTEMI and, 141
for pulmonary thromboembolism, 355 for STEMI, 143–144
Thrombosis
heparin-induced thrombocytopenia and, 223
in paroxysmal nocturnal
hemoglobinuria, 207 Thrombotic thrombocytopenic purpura
(TTP), 222–223
Thrush (oral candidiasis), 440 Thymectomy, 423
Thymoma, 423
Thyroid gland diseases, 23–33 neoplasia, 31–33
Thyroid hormones, 23
synthesis and secretion pathways, 24 thyroid function and, 25
Thyroid-reactive iodine uptake (RAIU), 24, 25
Thyroid-stimulating hormone (TSH), 23, 25
in hypothyroidism diagnosis, 30 Thyroid stimulating immunoglobulin (TSI), 25, 26, 27, 28
Thyroid storm, 28
Thyroiditis, 30–31
Thyrotoxicosis, 25–28
amiodarone-induced, 29 atrial fibrillation in, 373
Thyrotropin-releasing hormone (TRH), hyperprolactinemia and, 14
Thyrotropin (TSH) hyperprolactinemia and, 14
hypopituitarism and, 18
l-Thyroxine (T4), 18, 23, 28, 30, 31, 32
Tic douloureux, 420
Tigecycline, 227
Tinea capitis, 439
Tinea corporis, 439
Tinea cruris, 439
Tinea pedis, 439
Tinea versicolor, 439–440 Tinnitus
in salicylate toxicity, 386 vertigo and, 416
Tissue plasminogen activator (tPA), for cerebrovascular accident, 410–411
Tizanidine therapy, in ALS, 423 TMP/SMX therapy
for diarrhea, 104 for skin MRSA, 228
Tocainide, adverse effects, 189
Tonic-clonic (grand mal) seizures, 412 Topiramate, 419
Torsade de Pointes, 186–187
ventricular tachycardia and, 367–368 Total lung capacity (TLC), 321, 323 Toxic diffuse goiter (Graves’ disease), 25,
26–28
Toxic epidermal necrolysis (TEN), 437–438
Toxic multinodular goiter (Plummer disease), 25
Toxic shock syndrome (TSS), 446 Toxicology
acetaminophen poisoning, 378–379
acids/alkalis, 381–382
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
494
Index
alcohol withdrawal-related syndromes, 390–391
anticholinergic poisoning, 388–389 carbon monoxide poisoning, 380–381 caustics/corrosives, 380–381
digitalis, 156–157
digoxin, 157
digoxin poisoning, 387
drug abuse, 382–384 drug clearance times, 378
ethylene glycol ingestion, 379–380 heavy metals exposure, 384
initial evaluation, 376
isopropyl alcohol ingestion, 380 methanol ingestion, 379–380
organophosphate poisoning, 389
salicylates, 386–387
toxic ingestion/overdose management, 377–378
toxidrome physical findings, 376 tricyclic antidepressants, 388
Toxicology screen, 378
Toxidromes, 376 Toxin exposures
acute renal failure and, 289–290 Staphylococcal scalded skin syndrome,
446–447
toxic shock syndrome, 446 Toxoplasmosis
brain abscess and, 233
in HIV/AIDS, 232, 274–275
Transcutaneous vs. transvenous pacing, 374 Transferrin saturation test, 122 Transfusion therapy
in anemia, 194
in radiation injury management, 401 in sickle cell disease, 204
Transient hyperthyroidism, 25 Transjugular intrahepatic portosystemic
shunting (TIPS), 114 Transplantation
bone marrow, in radiation injury management, 401
renal, 300
Transudative pleural effusion, 328 Trauma, to head, 391–394 Traumatic arthritis, 62
Travel medicine, 3–4 Traveler’s diarrhea
management, 104
prevention, 4
Tremor. See Essential tremor Treponema pallidum, 252 Tricyclic antidepressants
for migraine headaches, 419 toxicity and overdose of, 388
Trigeminal neuralgia, 420
l-3,5,5’-Triiodothyronine (T3), 18, 23 Tropheryma whippelii biopsy, 109 Tropical sprue, 109
Troponins, cardiac, in chest pain evaluation, 127–128
Trousseau sign, 39
Tuberculosis, 243–245 Tubulointerstitial disease, acute renal
failure and, 285–290 Tumor lysis syndrome (TLS), 217
Tumor necrosis factor (TNF) inhibitors, in RA management, 67
Two-dimensional echocardiography, in mitral valve prolapse, 164
decubitus (pressure), 453 foot, in diabetes mellitus, 46
Ultrasound, in abdominal imaging, 460 Ultraviolet (UV)-B light sensitivity, in
Unstable angina (UA), 137, 138–140 high-risk features in, 139
Urate, in acute renal failure, 288
Urate crystals, in acute renal failure, 288 Uremia, acute renal failure and, 281–282 Urethritis, 251–252
Uric acid stones, in nephrolithiasis, 310 Uric acid toxicity, in acute renal failure, 288 Urinalysis
in porphyria cutanea tarda, 435
in renal disease diagnosis, 297–298 Urinary tract infection (UTI), 258–260 Urine immunoassay, in toxicology screen,
378
Urine output
in lead poisoning, 384
in salicylate poisoning, 386 in toxic ingestion/overdose
management, 377
Uroporphyrins, urinary, 435
Urticaria, drug reactions causing, 435–436 Uveitis, 471–472
V
Vaccines
diphtheria/tetanus, 5
hepatitis A virus, 3, 6, 251
hepatitis B virus, 3, 5, 251
herpes zoster, 7
in HIV-positive persons, 275 human papillomavirus, 7
influenza, 5, 236
measles, mumps, rubella, 6 meningococcal, 5, 6
pneumococcal, 5, 242, 343
polio, 4
rabies, 4
shingles, 7
tuberculosis, 243
typhoid, 4
varicella, 6
Vagal maneuvers, for supraventricular tachycardia, 371
Valganciclovir, 274 Valproic acid
for migraine headaches, 419
for seizures and epilepsy, 414–415 Valsalva maneuver
effect on systolic murmurs, 166
in supraventricular tachycardia, 371 Valvular heart disease, 160–167
aortic regurgitation, 166–167
aortic stenosis, 164–166
mitral regurgitation, 161–163
mitral stenosis, 160–161 mitral valve prolapse, 163–164
Vancomycin
acute renal failure and, 290 for gram-positive cocci, 227 for meningitis, 230
Varenicline, contraindicated in psychiatric disease, 8
Varicella vaccine, 6
Varices, esophageal, 114
Vascular dementia, 427 Vascular diseases
hypopituitarism and, 13
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
495
USMLE Step 2 CK l Internal Medicine
micro-/macro-, as diabetes
complication, 45
Vasculitis syndromes, 81–83 Vasodilators
as antihypertensive, 318
in congestive heart failure, 154–155 Vasopressin. See also Antidiuretic hormone
(ADH)
diabetes insipidus and, 20, 21, 120 excess of, syndromes associated with, 22 pituitary gland and, 11
syndrome of inappropriate secretion of ADH, 22
Venomous bites and stings, 402–404 Venous blood gases, in carbon monoxide
poisoning, 380, 381
Ventilation, 333–334
Ventilation-perfusion (V/Q) scan, 353 Ventricular arrhythmias, 184–185
Ventricular fibrillation, 365 Ventricular rate control, in atrial
fibrillation, 183 Ventricular septal defect, effect of
maneuvers in, 166
Ventricular tachycardia (VT), 184–185, 367–368
management algorithm, 183, 366
supraventricular, 185, 369–373
Verapamil, 419
adverse effects, 189
Vertigo, 415–417
Vestibular disease, vertigo and, 415
Vibrio parahaemolyticus, infectious diarrhea and, 103, 104
Vibrio vulnificus
hemochromatosis and, 122
infectious diarrhea and, 103, 104
Viekira Pak, 250
Violence, screening for, 10 Viral infections
hepatic, 248–251. See also Hepatitis
entries
infectious diarrhea and, 103, 104
of skin, 443–445
Viral load monitoring, in AIDS, 276 Viral sensitivity/resistance monitoring, in
AIDS, 276
Virtual colonoscopy, 462
Vital capacity (VC), 321, 323
Vitamin B12 (cyanocobalamine) deficiency, 200–201
in subacute combined spinal cord degeneration, 407
Vitamin B12 (cyanocobalamine) malabsorption, 108
Vitamin K deficiency, 221 VITAMINS mnemonic, 412
Vomiting, induced, in toxic ingestion/ overdose management, 377
von Willebrand disease (vWD), 218–219 Voriconazole, 280
Vulvovaginitis, 440
Wallenberg syndrome, 410 Warfarin
in acute coronary syndrome, 146 coagulopathy and, 223–224
for pulmonary thromboembolism, 355–356
Warts, genital, 257 Water restriction test, 21 Weber syndrome, 410
Wegener granulomatosis (WG), 62, 81–82,
Wells’ criteria, for pulmonary embolism risk, 352
Wenckebach AV block, 177, 373, 374
Wernicke encephalopathy, 390, 391
Westermark sign, 353 Wheals, in urticaria, 435 Whipple’s disease, 108, 109
“White coat hypertension,” 313
Whole bowel irrigation, in toxic ingestion/ overdose management, 377
Wide complex tachycardia, 370 Wilson disease, 122–123 Withdrawal/Withdrawal syndromes,
alcohol-related, 390–391
Wolff-Chaikoff effect, 28
Wolff-Parkinson-White (WPW) syndrome, 183–184, 185
atrial fibrillation in, 373 Wound management, 279
X
X-rays
abdominal, 460–462
in ankylosing spondylitis, 74–75 cervical spine, 74–75, 392
chest. See Chest x-rays in head trauma, 392
Xanthochromia, in subarachnoid hemorrhage, 396
Y
Yersinia
hemochromatosis and, 122
infectious diarrhea and, 103, 104
Yersinia pestis, as pneumonia
predisposition, 239
Zenker diverticulum, 90–91
Zidovudine (AZT), 278
Zollinger-Ellison syndrome (ZES), 97–98 peptic ulcer disease and, 95
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
496
